Operational hub cells: a morpho-physiologically diverse class of GABAergic neurons united by a common function

Rosa Cossart

GABAergic microcircuits structure the activation of neuronal ensembles that support most cortical computations. Because of the heterogeneous nature of the GABAergic cell community, a full understanding of structure-function relationships in these microcircuits may be hampered by a reductionist approach that consists of classifying them according to an exhaustive collection of parameters. It therefore could be beneficial to our understanding of these complex cells to also consider other approaches. Thus, graph theory has recently taught us that biological networks often include hub nodes that are essential for information flow, and ensuing experimental evidence has demonstrated the existence of 'operational' hub neurons. So far, only GABAergic neurons have been identified as 'operational hubs', further emphasizing their critical function in controlling cortical network dynamics.

Introduction

The coordinated activation of neuronal ensembles structured within networks is proposed to support the ongoing computations of the cerebral cortex in health and disease. Within these networks of neurons, GABAergic cells are key nodes that shape neuronal dynamics in space and time. This major network function is mirrored in the bewildering diversity of cortical GABAergic cells, which can be subdivided into many anatomically, physiologically, biochemically, and ontogenically distinct classes. One way to understand how GABAergic networks are organized to support cortical function and dynamics has been to attempt to classify them into distinct families based on various parameters [START_REF] Defelipe | New insights into the classification and nomenclature of cortical GABAergic interneurons[END_REF]. The increasing accessibility and detail of morphological, molecular, physiological, and developmental data are both providing a substrate for this classification and encouraging GABAergic neuron taxonomy. It is undeniable that detailed characterization and classification have provided valuable information regarding GABA neuron function. However, it may well be that as our knowledge about the morphophysiological and genetic determinants of individual GABAergic cells increases, the more complex it becomes to reconcile the overall functional features of the system as a whole. Indeed, the problem of classifying and naming GABAergic neurons in the cerebral cortex has yet to reach a satisfactory consensus and single-cell diversity can blur our understanding of GABAergic networks. In addition, neurons belonging to different classes could potentially serve overlapping functions, thus providing cortical networks with a valuable redundancy that protects them, for example, from pathological insults.

The understanding of the functional organization of cortical GABAergic networks may thus be partially constrained by this reductionist approach and could benefit from the progress network science is currently experiencing [START_REF] Feldt | Dissecting functional connectivity of neuronal microcircuits: experimental and theoretical insights[END_REF]. Hence, after an initial description of cortical GABAergic microcircuits merely based on anatomical features and later taking into account multiple parameters to group them into distinct families using, for example, multiparametric clustering methods, it would be advantageous to know whether their functional organization, as a network, could be related to any previously described canonical structure (Figure 1). Indeed, many real networks, as different as the brain and the Internet, share similar architectures independently of their function. This universality is encouraging researchers from different disciplines to feed their research with concepts from network theory, and the recent finding of a morphophysiologically heterogeneous class of GABAergic cells unified by a common hub function supports this initiative [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF].

What is an 'operational' hub neuron? From theory to experimental evidence

The term hub originates from the theoretical field of complex networks and clearly deserves some definition to avoid confusion, particularly in the context of experiments [START_REF] Feldt | Dissecting functional connectivity of neuronal microcircuits: experimental and theoretical insights[END_REF]. One of the most commonly described properties of a network is its degree distribution. It is used to distinguish between different types of network organization. The degree of a node is defined as its total number of links or connections to other nodes in the network. A connection does not refer to an absolute measure but to a parameter that is chosen during the analysis depending upon the type of network being studied and the questions being asked. Neuronal networks are mainly described by three different types of connectivity reflecting three parallel levels of investigation: anatomical (i.e. physical connection between two neurons), functional (statistical relationship between the activity of two neurons) and effective (causal relationship between the activity of two neurons). Functional, effective, or anatomical hubs are neurons that have a high number of functional, effective, or anatomical connections to other neurons in networks where most neurons have very few. Experimentally speaking, we would like to introduce the term 'operational' hub neuron: a cell not only displaying a high functional connectivity degree (i.e. a functional hub), but also actively involved in generating network synchronization, the stimulation of which single-handedly impacts network dynamics. Experimental evidence for the existence of 'operational hub' neurons relied on the mapping of 'functional connectivity' in living brain slices based on the analysis of multineuron calcium activity [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF].

Functional hub neurons were found to be a mixture of glutamatergic (presumably early-born [START_REF] Marissal | Pioneer glutamatergic cells develop into a morpho-functionally distinct population in the juvenile CA3 hippocampus[END_REF], see below) and GABAergic cells [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF]. However, electrophysiological recordings showed that only GABAergic neurons combined a high degree of functional, effective, and anatomical connectivity and acted as 'operational' hubs: their stimulation causally triggered the activation of many other neurons while disrupting spontaneous network oscillations.

It is easy to confuse hubs with GABAergic short-cuts between physically remote brain areas (such as the hippocampus and the medial septum [START_REF] Jinno | Neuronal diversity in GABAergic long-range projections from the hippocampus[END_REF][START_REF] Shinoda | Hippocampofugal gammaaminobutyric acid (GABA)-containing neuron system in the rat: a study using a double-labeling method that combines retrograde tracing and immunocytochemistry[END_REF] or the entorhinal cortex [START_REF] Ino | Direct projections of non-pyramidal neurons of Ammon's horn to the amygdala and the entorhinal cortex[END_REF][START_REF] Melzer | Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex[END_REF]) for several reasons. First, both GABAergic hub cells and short-cuts are atypical network components with an extended axonal arborization unlike most other cortical GABAergic neurons. Secondly, in network space, short-cuts are nodes displaying long-range contacts (with 'length' referring to the number of functional links that separate nodes and not to their actual physical distance Understanding the functional organization of GABAergic microcircuits: from single-cell classifications (top) to network level analysis derived from graph theory (bottom). Anatomical description has provided valuable information regarding GABAergic neuron diversity as illustrated by the drawing taken with permission from [START_REF] Freund | Interneurons of the hippocampus[END_REF]. More recent work combined a description of developmental, electrophysiological, and molecular properties of GABAergic neurons and applied cluster analyses to separate them into distinct subfamilies as illustrated by the dendrogram taken with permission from [START_REF] Tricoire | A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity[END_REF]. The functional organization of GABAergic cells, as a network, may be related to a previously described canonical structure as schematized below.

[2]), thus allowing information flow quickly. Hence, hub cells and GABAergic short-cuts likely function in coordinating network oscillations [START_REF] Buzsaki | Interneuron diversity series: circuit complexity and axon wiring economy of cortical interneurons[END_REF][START_REF] Caputi | The long and short of GABAergic neurons[END_REF]. Further contributing to the confusion was the recent demonstration that a subpopulation of developmentally active GABAergic hub cells matures into short-cuts connecting the hippocampus to remote areas in the adult mouse [START_REF] Picardo | GABA pioneer cells comprise a subpopulation of hub neurons in the developing hippocampus[END_REF]. Still, short-cuts that connect two distant regions through sparse synaptic targets do not necessarily display the high connectivity degree that characterizes hub cells.

Is being a hub neuron a privilege of elite members of the GABAergic aristocracy [START_REF] Case | Discreet charm of the GABAergic bourgeoisie: superconnected cells conduct developmental symphonies[END_REF]?

As mentioned above, neurons that display a high functional connectivity degree in the developing hippocampus form a heterogeneous population that gathers both glutamatergic pyramidal neurons and GABAergic cells. Interestingly, two genetic fate mapping studies indicate that this distinct group of cells may share an early birthdate [START_REF] Marissal | Pioneer glutamatergic cells develop into a morpho-functionally distinct population in the juvenile CA3 hippocampus[END_REF][START_REF] Picardo | GABA pioneer cells comprise a subpopulation of hub neurons in the developing hippocampus[END_REF]. Thus some kind of 'droit d'aı ˆnesse', the old rule of inheritance whereby monarchy descends to the firstborn in preference to siblings, may also apply to neurons. This phenomenon may be the direct consequence of the 'preferential attachment rule' (Figure 2) that theoretically governs the growth of scalefree networks [START_REF] Barabasi | Emergence of scaling in random networks[END_REF]. In addition, since there is also a 'temporal matching rule' by which cells tend to connect according to their temporal embryonic origin [START_REF] Deguchi | Temporally matched subpopulations of selectively interconnected principal neurons in the hippocampus[END_REF], high connectivity glutamatergic and GABAergic neurons may well form a 'rich club' [START_REF] Van Den Heuvel | Rich-club organization of the human connectome[END_REF] sharing a high functional network impact, further reinforcing the privileges of that aristocracy.

However, in the developing hippocampus, only GABAergic neurons were experimentally shown to act as 'operational hubs'. In contrast, high connectivity glutamatergic neurons operate as assemblies, capable of triggering network synchronization when activated collectively when fast GABAergic transmission is impaired [START_REF] Marissal | Pioneer glutamatergic cells develop into a morpho-functionally distinct population in the juvenile CA3 hippocampus[END_REF]. This raises the question of whether only GABAergic neurons can act as 'operational' hub cells. So far, experiments providing the existence of 'operational hub' cells have only been performed in the developing hippocampus [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF]. Since we now know about certain intrinsic and functional properties of developmental hub cells, it is tempting to speculate whether other previously described subtypes of GABAergic cells may also be part of the hub cell family. An example within the hippocampus is Cajal Retzius cells which are early generated and target extrahippocampal regions, in particular the entorhinal cortex [START_REF] Ceranik | Hippocampal Cajal-Retzius cells project to the entorhinal cortex: retrograde tracing and intracellular labelling studies[END_REF]. Similarly, basket cells of the adult hippocampus may serve as 'operational hubs' since they are the site of high input convergence and output divergence [START_REF] Sik | Complete axon arborization of a single CA3 pyramidal cell in the rat hippocampus, and its relationship with postsynaptic parvalbumin-containing interneurons[END_REF][START_REF] Freund | Interneurons of the hippocampus[END_REF][START_REF] Tukker | Distinct dendritic arborization and in vivo firing patterns of parvalbumin-expressing basket cells in the hippocampal area CA3[END_REF][START_REF] Sik | Hippocampal CA1 interneurons: an in vivo intracellular labeling study[END_REF] and are able to time the incidence of sharp waves recorded in adult hippocampal slices [START_REF] Ellender | Priming of hippocampal population bursts by individual perisomatictargeting interneurons[END_REF]. Similarly, enkephalin-positive CA1 GABAergic neurons are a small neuronal population that targets exclusively other interneurons in the subiculum and may thus coordinate network oscillations between that region and the hippocampus [START_REF] Fuentealba | Rhythmically active enkephalin-expressing GABAergic cells in the CA1 area of the hippocampus project to the subiculum and preferentially innervate interneurons[END_REF].

Are hub neurons a specific subtype of GABAergic cell?

The above conjectures naturally raise the question of whether hippocampal 'operational hubs' comprise a finite and well defined morpho-physiological variety of GABAergic cells. Let us focus on GABAergic cells with a hub function in the developing CA3 hippocampus. In this restricted particular case two families of 'operational hubs' could be distinguished based on their anatomical connectivity (Figure 3):

(1) 'connector hubs' [START_REF] Bullmore | Complex brain networks: graph theoretical analysis of structural and functional systems[END_REF] that display a long axon spanning across regions with sparse collaterals often invading the fimbria and comprising long-range projecting GABAergic neurons [3 ,11 ]. Morphological heterogeneity prevails in this population, consistent with previous descriptions of GABAergic projection hippocampal neurons [START_REF] Jinno | Neuronal diversity in GABAergic long-range projections from the hippocampus[END_REF][START_REF] Fuentealba | Rhythmically active enkephalin-expressing GABAergic cells in the CA1 area of the hippocampus project to the subiculum and preferentially innervate interneurons[END_REF]. Some, if not all of these 'connector hubs' have an early temporal embryonic origin [START_REF] Picardo | GABA pioneer cells comprise a subpopulation of hub neurons in the developing hippocampus[END_REF] and express a variety of neurochemical markers. Function wise, the activation of connector hubs in the immature CA3 generally disrupts network synchronization, even Scheme illustrating how scale-free networks grow following a preferential attachment rule derived from a 'homophilic' growth process. The dark red node, which turns into a hub, was present at the early stages of network growth and maximizes similarity with other nodes (similarity is schematized by the color of the nodes).

though these cells are recruited at the onset of GDPs [3 ,11 ]. Interestingly, these cells have been recently shown to also critically determine the onset of epileptiform discharges induced by low Mg 2+ conditions in the intact immature septohippocampal formation by directly synchronizing other interneurons [START_REF] Quilichini | GABA Hub neurons mediate gamma-frequency oscillations at ictal-like event onset in the immature hippocampus[END_REF]. (2) 'provincial hubs' that are comprised of basket-like neurons that get connected within their own field through a dense but more local arborization pattern; their phasic activation may trigger network synchronization in the developing CA3 [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF]. The embryonic origin and adult fate of these basket-like hub neurons still remain to be determined. Although these cells may form a functionally distinct subclass of perisomatic neurons, diversity is also very likely to be present in this interneuron category [START_REF] Freund | Interneurons of the hippocampus[END_REF], as suggested by the analysis of their ontogeny [START_REF] Tricoire | A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity[END_REF].

The level of heterogeneity observed in the 'operational hub' cell population so far may be the direct consequence of a developmental process by which hub neurons are not only the oldest neurons, but also those neurons that share a maximum number of features with other cells (Figure 2). This supposition is supported by a recent theoretical prediction. In order to explain the emergence of 'preferential attachment', the rule mentioned above by which scale-free networks grow and hub neurons emerge [START_REF] Barabasi | Emergence of scaling in random networks[END_REF], it has been proposed that networks may grow following an homophilic process by which new nodes will preferentially connect to nodes that are similar to them [START_REF] Papadopoulos | Popularity versus similarity in growing networks[END_REF]. In other words, similar types of neurons will preferentially connect to each other and therefore hub neurons should be cells that maximize some similarity index (Figure 2) and that way would incorporate the characteristics of many other neurons. This prediction is in agreement with various biological observations, High anatomical connectivity

Connector Provincial

Long-range Dense

HUB neuron

GABAergic cell

Diversity of operational GABAergic hub neurons in the hippocampus. Two families of 'operational hubs' in the developing CA3 could be distinguished based on their axonal connectivity patterns: 'connector hubs' that display a long axon comprising long-range projecting GABAergic neurons and 'provincial hubs', displaying a dense local axonal arborization with a 'basket-like' morphology. These two populations gather anatomically diverse cells as seen from the Neurolucida reconstructions of various hub cells filled during the experiments (illustrations taken with permission from [START_REF] Bonifazi | GABAergic hub neurons orchestrate synchrony in developing hippocampal networks[END_REF] and [START_REF] Picardo | GABA pioneer cells comprise a subpopulation of hub neurons in the developing hippocampus[END_REF]).

including the fact that adult GABAergic neurons of the same subfamily tend to preferentially connect to each other via gap junctions [START_REF] Hestrin | Electrical synapses define networks of neocortical GABAergic neurons[END_REF], that cortical glutamatergic cells with the same target area are also more likely to connect to each other [START_REF] Brown | Cell-type identity: a key to unlocking the function of neocortical circuits[END_REF] or that clonally related neurons of the neocortex are more likely to be electrically [START_REF] Yu | Preferential electrical coupling regulates neocortical lineage-dependent microcircuit assembly[END_REF], then synaptically connected [START_REF] Yu | Specific synapses develop preferentially among sister excitatory neurons in the neocortex[END_REF].

Of course, the circuit components that account for the possible similarity index used by developing cortical networks remain an open question. In light of the GABAergic interneuron diversity, it will be of most interest to investigate whether this similarity index is derived from cellular intrinsic factors, extrinsic network determinants or both. Anyway, the similarity index must exert one of its most direct and extreme influence in the case of GABAergic hub cells. Hence, the fact that GABAergic projection neurons function as 'operational hub' cells may well be the direct consequence of that similarity rule since a GABAergic hippocampal neuron that targets extrahippocampal areas is on a connectivity level closer to a glutamatergic pyramidal neuron (i.e. projection neurons) than to any other subtype of GABAergic neuron.

GABAergic hub neurons in pathology

The issue of hub neuron function becomes particularly relevant in the context of pathologies for several reasons. First, as GABAergic hub neurons have been shown to synchronize early network oscillations, they should be essential for the proper development of circuits and an abnormal maturation of these cells may lead to developmental brain disorders. Second, a number of brain pathologies are associated with aberrant network oscillations as in the case of epilepsy. In fact, modeling work suggests that epileptic activity may depend on the existence of highly anatomically connected excitatory hub cells [START_REF] Morgan | Nonrandom connectivity of the epileptic dentate gyrus predicts a major role for neuronal hubs in seizures[END_REF]. However, recent experimental data obtained from slices using a chronic mouse model of temporal lobe epilepsy [START_REF] Muldoon | Spatially clustered neuronal assemblies comprise the microstructure of synchrony in chronically epileptic networks[END_REF], from cultured rat slices [START_REF] Sabolek | A candidate mechanism underlying the variance of interictal spike propagation[END_REF] as well as from humans with focal epilepsy [START_REF] Truccolo | Single-neuron dynamics in human focal epilepsy[END_REF][START_REF] Keller | Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex[END_REF], indicate variable paths of epileptiform synchronization dynamics. This raises the intriguing possibility that pathological and physiological network dynamics could be discriminated based on the stability of their spatial components and makes it less probable that the same 'operational hub' neuron repeatedly recruits or transmits information to similar assemblies in the epileptic synchronization process. Still, it was shown in acute models of epileptiform synchronization that specific GABAergic neurons acting as synchronization 'drivers' were critically involved in the generation of aberrant network bursts [24 ,36]. Therefore the involvement of 'operational hub' cells in pathology still remains an open question.

Conclusion

GABAergic 'operational hub' cells are a major functional subtype of hippocampal neurons. They represent a small but heterogeneous fraction of the total neuronal population, sharing a high functional and anatomical connectivity and most likely an early birthdate. In fact, hub cells may be designed to share as many characteristics as possible to a maximum number of other cell types including their glutamatergic counterparts, turning them into projection neurons and contributing to their striking diversity. We reason that being a hub is a privilege of neurons involved in GABAergic transmission in order to preserve network stability, but a different situation may prevail in pathological conditions. So far, 'operational hub' cells were found in the developing hippocampus, but given the presence of long-range projecting GABAergic cells in other structures, it may well be that this cell population is universally present and forms a 'rich club' supporting brain function, during development as well as later in health and disease.

  Figure 1

Figure 2

 2 Figure 2

Figure 3

 3 Figure 3

Acknowledgements

I thank Sarah Feldt Muldoon, Vitor Sousa and Agne `s Baude for helpful discussions and suggestions. I thank the FP7-ERC 'GABA Networks' grant (# 242842), the Fondation pour la Recherche Medicale, The Bettencourt-Schueller Foundation, the C.N.R.S. and the I.N.S.E.R.M. for financial support.


Camille Allene

Rosa Cossart
email: cossart@inmed.univ-mrs.fr

Early NMDA receptor-driven waves of activity in the developing neocortex: physiological or pathological network oscillations?

Early NMDA receptor-driven waves of activity in the developing neocortex: physiological or pathological network oscillations?

Camille Allène, Rosa

The immature brain is endowed with the ability to generate a variety of coherent activity patterns [START_REF] O'donovan | Mechanisms of spontaneous activity in the developing spinal cord and their relevance to locomotion[END_REF][START_REF] Roerig | Neurotransmitters and gap junctions in developing neural circuits[END_REF][START_REF] Moody | Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells[END_REF][START_REF] Khazipov | Early patterns of electrical activity in the developing cerebral cortex of humans and rodents[END_REF][START_REF] Ben-Ari | GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations[END_REF]. Several studies indicate that as development proceeds, synchronous neuronal activity displays changing dynamics and is controlled by distinct mechanisms [START_REF] Syed | Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina[END_REF][START_REF] Khazipov | Early patterns of electrical activity in the developing cerebral cortex of humans and rodents[END_REF][START_REF] Mccabe | The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF][START_REF] Sibilla | The patterns of spontaneous Ca 2+ signals generated by ventral spinal neurons in vitro show time-dependent refinement[END_REF]). These successive stages closely parallel the maturation of physiological and morphological cellular properties (Picken [START_REF] Bahrey | Early development of voltage-gated ion currents and firing properties in neurons of the mouse cerebral cortex[END_REF][START_REF] Moody | Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells[END_REF][START_REF] Torborg | Spontaneous patterned retinal activity and the refinement of retinal projections[END_REF][START_REF] Guido | Refinement of the retinogeniculate pathway[END_REF][START_REF] Sibilla | The patterns of spontaneous Ca 2+ signals generated by ventral spinal neurons in vitro show time-dependent refinement[END_REF]). The neocortex is the structure for which probably the most compelling variety of network patterns have been described [START_REF] Yuste | Neuronal domains in developing neocortex[END_REF][START_REF] Kandler | Coordination of neuronal activity in developing visual cortex by gap junction-mediated biochemical communication[END_REF][START_REF] Owens | Patterns of intracellular calcium fluctuation in precursor cells of the neocortical ventricular zone[END_REF][START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Peinado | Traveling slow waves of neural activity: a novel form of network activity in developing neocortex[END_REF][START_REF] Voigt | Synchronous oscillatory activity in immature cortical network is driven by GABAergic preplate neurons[END_REF][START_REF] Opitz | Spontaneous development of synchronous oscillatory activity during maturation of cortical networks in vitro[END_REF][START_REF] Corlew | Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones[END_REF][START_REF] Khazipov | Early motor activity drives spindle bursts in the developing somatosensory cortex[END_REF][START_REF] Weissman | Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex[END_REF][START_REF] Adelsberger | Cortical calcium waves in resting newborn mice[END_REF][START_REF] Dupont | Rapid developmental switch in the mechanisms driving early cortical columnar networks[END_REF][START_REF] Mccabe | The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones[END_REF]Milh et al. 2007b). This variety not only reflects This review was presented at a symposium on Neurophysiology of inhibitory & excitatory amino acid receptors which took place at the 11th International Congress on Amino Acids, Peptides and Proteins, Vienna, on 3 August 2009.

an endogenous developmental programme, but also the multiplicity of experimental approaches and animal models used to study network oscillations. Hence, network patterns which were named differently because they were measured in different experimental conditions (e.g. in vivo vs. in vitro, calcium imaging vs. electrophysiology, etc.) may actually refer to the same biological phenomenon. In an attempt to assign a function to each synchronous neuronal activity pattern it is therefore essential to review and compare their different mechanisms and conditions of observation. Cortical early network oscillations (cENOs) are large-scale oscillatory calcium waves occurring immediately after birth at low frequency and providing most of the coherent activity during the first postnatal week in the developing rodent neocortex [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF]. These were described both in vitro and in vivo using imaging techniques [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Adelsberger | Cortical calcium waves in resting newborn mice[END_REF]) and more recently using electrophysiological approaches [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF][START_REF] Yang | Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo[END_REF]. Many developmental network patterns are mediated by GABAergic transmission given its early excitatory actions and advanced maturation compared to glutamatergic synapses [START_REF] Ben-Ari | GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations[END_REF]. Remarkably, cENOs were shown to be generated by the activation of NMDA receptors (NMDA-Rs) and are critically dependent on extracellular glutamate concentration [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF][START_REF] Yang | Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo[END_REF]. This feature imparts to the immature cerebral cortex a critical sensitivity to pathological transmitter accumulations. It also confers on glutamate a critical role in early cortical development. Furthermore, cENOs are preferentially observed under specific conditions such as mild anoxia. This observation questions the physiological relevance of cENOs. In this review, we will discuss the mechanisms, developmental profile and dynamics specific to cENOs in order to propose a relevant function for this network pattern and NMDA-R-driven oscillations in general during brain maturation.

A general sequence for the maturation of coherent activity patterns in cortical structures

Most developing peripheral and central neurons are spontaneously active. In the cortex, neuronal activity is associated with an intracellular calcium rise that can either be produced by a membrane potential depolarization measurable with electrophysiological approaches or be produced intracellularly without any electrical signature, although measurable with optical approaches (see Fig. 1). Spontaneous activity is further subdivided into uncorrelated and coherent activity patterns (see Fig. 1). Coherent electrical activity patterns progressively emerge during cortical development.

Calcium activity at embryonic stages consists of either uncorrelated membrane potential spikes [START_REF] Komuro | Intracellular Ca 2+ fluctuations modulate the rate of neuronal migration[END_REF][START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF][START_REF] Bortone | KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner[END_REF] or synchronous 'non-electrical' calcium rises [START_REF] Owens | Patterns of intracellular calcium fluctuation in precursor cells of the neocortical ventricular zone[END_REF][START_REF] Weissman | Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex[END_REF]; see Fig. 1). Embryonic calcium activity in cortical structures has been suggested to play a role in the regulation of neurogenesis [START_REF] Owens | Patterns of intracellular calcium fluctuation in precursor cells of the neocortical ventricular zone[END_REF][START_REF] Weissman | Calcium waves propagate through radial glial cells and modulate proliferation in the developing neocortex[END_REF]) in neuronal differentiation and migration [START_REF] Komuro | Intracellular Ca 2+ fluctuations modulate the rate of neuronal migration[END_REF][START_REF] Bortone | KCC2 expression promotes the termination of cortical interneuron migration in a voltage-sensitive calcium-dependent manner[END_REF]. Primitive forms of activity in embryonic cortical structures are mostly uncorrelated calcium rises that participate in the maturation of intrinsic neuronal properties.

Around birth in rodents, neuronal activity becomes coherent in cortical structures. Several patterns of synchronous neuronal activity have been described (see Figs 1 and2). With the exception of cortical domains [START_REF] Yuste | Neuronal domains in developing neocortex[END_REF][START_REF] Kandler | Coordination of neuronal activity in developing visual cortex by gap junction-mediated biochemical communication[END_REF], all of them are associated with electrical activity (see Fig. 1). There is a robust timetable in the mechanisms responsible for the synchronization of neuronal activity: population coherence first relies on gap-junction coupling and on the activation of intrinsic voltage-dependent conductances before becoming mostly synapse-driven (see Fig. 1). We have recently established in both the neocortex [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]) and the hippocampus [START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF]) that the earliest coherent electrical activity pattern emerges at birth in the form of synchronous plateau assemblies (SPAs), so named because of their characteristic spatial-temporal dynamics: SPAs involve small groups of neurons producing synchronous calcium plateaus. Each calcium plateau is associated with sustained intrinsic membrane potential oscillations. SPAs are therefore a step of coherent electrical activity common to hippocampal and neocortical networks that precedes the emergence of synapse-driven network oscillations (Fig. 2).

At early postnatal stages, two spontaneous synapse-driven network patterns have been extensively described in developing neocortical slices: giant depolarizing potentials (GDPs) driven by GABAergic transmission [START_REF] Ben-Ari | Giant synaptic potentials in immature rat CA3 hippocampal neurones[END_REF][START_REF] Garaschuk | Developmental profile and synaptic origin of early network oscillations in the CA1 region of rat neonatal hippocampus[END_REF][START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]Rheims et al. 2008a) and cortical early network oscillations (cENOs) driven by glutamatergic transmission [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Corlew | Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones[END_REF][START_REF] Mccabe | The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. Relying on the apparent similarities between these patterns, cENOs were initially thought to be the neocortical counterpart of hippocampal GDPs. However, we have recently found that NMDA-R-driven ENOs and GABA A R-driven GDPs are indeed two distinct patterns in the neocortex, characterized by different spatiotemporal dynamics both in electrical and optical recordings. Whereas cENOs are low-frequency oscillations (0.01 Hz) displaying slow kinetics that gradually involve the entire network, cGDPs are recurrent oscillations (0.1 Hz) that repetitively synchronize localized neuronal assemblies. Moreover, ENOs and cGDPs are sequentially expressed in the immature neocortex since cENOs precede cGDPs. Interestingly, a recent in vivo study describing the maturation of coordinated electrical activity patterns in the rat somatosensory cortex has reported two patterns of oscillatory activity, 'spindle bursts' and 'long oscillations' , with dynamics very similar to cGDPs and cENOs, respectively [START_REF] Yang | Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo[END_REF]. It is therefore very likely that the sequence established in vitro will also apply in vivo [START_REF] Golshani | Internally mediated developmental desynchronization of neocortical network activity[END_REF].

What would be the main function carried by this precise sequence for the maturation of cortical networks? Given the largely documented role of activity in the maturation of cortical neurons [START_REF] Moody | Ion channel development, spontaneous activity, and activity-dependent development in nerve and muscle cells[END_REF][START_REF] Cancedda | Excitatory GABA action is essential for morphological maturation of cortical neurons in vivo[END_REF][START_REF] Lin | Activity-dependent regulation of inhibitory synapse development by Npas4[END_REF][START_REF] Wang | GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation[END_REF] and circuits [START_REF] Katz | Synaptic activity and the construction of cortical circuits[END_REF][START_REF] Huang | Activity-dependent development of inhibitory synapses and innervation pattern: role of GABA signalling and beyond[END_REF][START_REF] Pfeffer | NKCC1-dependent GABAergic excitation drives synaptic network maturation during early hippocampal development[END_REF], it is easy to speculate that the robust timetable for the maturation of network patterns is not merely the emergent expression of a precise sequence in the development of individual neuronal properties but something that also participates in proper cell maturation. In other words, activity itself would create a feedback loop that triggers the changes in neuronal and circuit properties that serve to terminate one network pattern and start the next.

Experiments selectively preventing the expression of a given network pattern within a precise sequence indirectly support this hypothesis. This sequence is particularly well-documented in the maturing retina, a structure in which spontaneous retinal waves will develop in three stereotyped sequential steps characterized by different dynamics and mechanisms [START_REF] Syed | Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina[END_REF]). While stage I waves are mostly mediated by gap-junction coupling, stage II and III rely on nicotinic and glutamatergic receptor activation, respectively [START_REF] Syed | Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina[END_REF][START_REF] Torborg | Spontaneous patterned retinal activity and the refinement of retinal projections[END_REF]. Waves at a given stage could be restored to the previous stage by blocking their specific neurotransmission system [START_REF] Mclaughlin | Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development[END_REF][START_REF] Syed | Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina[END_REF][START_REF] Stacy | Disruption and recovery of patterned retinal activity in the absence of acetylcholine[END_REF][START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF]. For example, mice lacking the enzyme that synthesizes acetylcholine will exhibit stage I gap junction-dependent retinal waves at a period of development normally dominated by stage II cholinergic waves [START_REF] Stacy | Disruption and recovery of patterned retinal activity in the absence of acetylcholine[END_REF]. Similarly, at the next stage of retinal activity pattern maturation, an absence of glutamatergic signalling in VGLUT1 KO mice was shown to delay the termination of stage II waves [START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF]. Also, β2-/-mice lacking the nicotinic receptor subunits mediating stage II waves will not display nicotinic-dependent correlated activity while stage III glutamatergic waves will begin earlier [START_REF] Mclaughlin | Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development[END_REF]. A precisely timed handover of synchrony between different network activity patterns also applies to the developing hippocampus [START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF]. Indeed, we have shown in this structure that the occurrence of synapse-driven GDPs actively shuts off the expression of the earlier gap-junction mediated SPA oscillations.

Figure 2. A general sequence for the maturation of coherent electrical activity patterns

Schematic representation of the sequential maturation of synchronized electrical activity patterns from late embryonic stages to the end of the first postnatal week in neocortical rodent slices [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. At embryonic stages electrical activity is uncorrelated. At birth it becomes synchronized through gap junctions and is supported by the activation of voltage-gated intrinsic conductances (SPAs). Later, network patterns are synapse-driven by glutamatergic (ENOs) or GABAergic (GDPs) transmission. Note that extrasynaptic glutamate receptors are also likely to be involved in the generation of ENOs. With the exception of ENOs, the same sequence was found in the developing hippocampus (Cr épel et al. 2007).

Moreover these two patterns are mutually exclusive within the same network and blocking GDPs will restore SPAs during the first postnatal week [START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF]. It is possible that the activation of NMDA-Rs occurring during GDPs [START_REF] Leinekugel | Ca 2+ oscillations mediated by the synergistic excitatory actions of GABA A and NMDA receptors in the neonatal hippocampus[END_REF]) could produce a long-term down-regulation of connexin expression [START_REF] Arumugam | NMDA receptors regulate developmental gap junction uncoupling via CREB signalling[END_REF]) that would silence SPAs. The handover of synchrony and direct interaction between SPAs, ENOs and GDPs has not yet been investigated in the neocortex. It is therefore at present difficult to claim whether a similar direct interaction between co-existing patterns also applies to the neocortex.

If such a precise timetable for synchronous neuronal activity maturation applies to the neocortex, it implies that a proper maturation of cortical structures will be highly sensitive to environmental factors. Indeed, coherent activity patterns can be largely modulated by environmental factors. For example, both in the neocortex and hippocampus, the emergence of SPAs is determined by the hormone oxytocin, which is released by the mother during delivery [START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. The effect of oxytocin on SPAs directly results from the action of the hormone on GABAergic transmission [START_REF] Tyzio | Maternal oxytocin triggers a transient inhibitory switch in GABA signalling in the fetal brain during delivery[END_REF] since SPAs were shown to be favoured by an inhibitory GABA polarity, for example produced by NKCC1 blockade [START_REF] Crépel | A parturition-associated nonsynaptic coherent activity pattern in the developing hippocampus[END_REF]). Hence, the same environmental change (i.e. oxytocin release) will create conditions that favour the emergence of SPAs but prevent GDPs. Interestingly, it is worth mentioning that probably several other environmental factors, including stress [START_REF] Shen | Reversal of neurosteroid effects at α4β2δ GABA A receptors triggers anxiety at puberty[END_REF]) and energy supply (Rheims et al. 2008b), will also ultimately impact network activity patterns by their direct action on the GABAergic system. In fact, we have shown that an anoxic episode occurring in a given network decreasing the rate of the perfusion from 4 to 1 ml min -1 (data taken from [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. Similar effects were found in anoxic/aglycaemic perfusion conditions (see [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. B, comparison between the membrane potential depolarization (top black trace), the calcium fluorescence signal (green) and the spontaneous excitatory postsynaptic currents (sEPSCs, bottom black, V m = -60 mV) associated with the spontaneous ENO illustrated in (Aa) and with a stage III retinal wave (reprinted from [START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF] with permission from Elsevier). Note the similarity between the two patterns. C, same as in B but comparing ENOs produced by a mild anoxic condition occurring when decreasing the perfusion rate (Ab) with slow network oscillations (SNOs) induced by pharmacological EEAT blockade with DL-TBOA (unpublished data from L. Aniksztejn & A.A. Cattani).

will boost the occurrence of cENOs while preventing the emergence of GDPs, the later network oscillation (Fig. 3; [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. This differential sensitivity of network patterns to environmental factors is directly determined by the cellular mechanism underlying their generation. In conclusion, the same environmental change can have different consequences on the network depending on which type of activity is dominant at the time it occurs.

NMDA-R driven early network oscillations: a role in synapse maturation?

As discussed above, ENOs are the dominant network pattern in neocortical slices at early postnatal stages. In contrast to most synapse-driven oscillations in other developing structures including the hippocampus, ENOs are mediated by the activation of NMDA-Rs rather than GABA A -Rs [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Dupont | Rapid developmental switch in the mechanisms driving early cortical columnar networks[END_REF][START_REF] Mccabe | The self-regulating nature of spontaneous synchronized activity in developing mouse cortical neurones[END_REF][START_REF] Sun | Spatio-temporal dynamics of oscillatory network activity in the neonatal mouse cerebral cortex[END_REF][START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. Accordingly, oscillations recorded in vivo in the neonatal rat barrel cortex are also largely dependent on NMDA-R activation [START_REF] Minlebaev | Network mechanisms of spindle-burst oscillations in the neonatal rat barrel cortex in vivo[END_REF][START_REF] Yang | Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo[END_REF]. Therefore NMDA-Rs specifically have a major network function at early developmental stages in the neocortex. In contrast, in the hippocampus, GABAergic synapses are established before glutamatergic ones [START_REF] Ben-Ari | Interneurons set the tune of developing networks[END_REF]). Accordingly, the first synapse-driven network pattern in this region is the GABA A -R-driven GDPs. The sequence of synapse maturation in the neocortex might be different even though GABAergic transmission also critically modulates neocortical activity through its complex excitatory/shunting action (Rheims et al. 2008a). Several observations indicate that NMDA-R signalling operates early in cortical development, notably to regulate the synaptic recruitment of AMPA-Rs [START_REF] Feldmeyer | Functional consequences of changes in NMDA receptor subunit expression during development[END_REF][START_REF] Zhu | Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity[END_REF][START_REF] Shi | Developmental depression of glutamate neurotransmission by chronic low-level activation of NMDA receptors[END_REF][START_REF] Radnikow | Axonal projection, input and output synapses, and synaptic physiology of Cajal-Retzius cells in the developing rat neocortex[END_REF][START_REF] Voigt | Activation of early silent synapses by spontaneous synchronous network activity limits the range of neocortical connections[END_REF][START_REF] Brill | Sequential changes in AMPA receptor targeting in the developing neocortical excitatory circuit[END_REF][START_REF] Wang | GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation[END_REF]. A detailed morpho-functional description of the sequential maturation of GABAergic and glutamatergic synapses in the neocortex will undoubtedly be helpful to understand the differences between the neocortex and hippocampus.

It is important to stress that the network function of NMDA-Rs in the neocortex does not necessarily imply synaptic activation of these receptors. Indeed, we have recently shown that NMDA-Rs also contribute to neuronal excitability in the neocortex by mediating a tonic current that supports membrane potential depolarization [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]). In the same study, we established the critical involvement of extracellular glutamate concentrations in the generation of cENOs. It is therefore possible that the generation of cENOs partly originates in the activation of extrasynaptic NMDA-Rs by ambient glutamate [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. The analogy between retinal and neocortical activity patterns is striking, in particular regarding the involvement of extrasynaptic glutamate receptors. Indeed, increases in ambient levels of glutamate were recently shown to be critically involved in generating stage III retinal waves [START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF]). In addition, the dynamics underlying NMDA-R-driven stage III retinal waves is remarkably similar to cortical ENOs [START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF]. The kinetics of both calcium and electrophysiological events associated with stage III retinal waves are as slow as those occurring during cENOs (Fig. 3). Interestingly, stage III retinal waves were shown to appear at a period when the glutamatergic synaptic system is not yet mature in the retina [START_REF] Syed | Stage-dependent dynamics and modulation of spontaneous waves in the developing rabbit retina[END_REF][START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF]) supporting a role for extrasynaptic NMDA-R activation in the maturation of synaptic circuits.

Cortical ENOs may support the conversion of 'silent' to 'active' synapses and regulate the recruitment of AMPA-Rs into functional synapses. Indeed this network pattern occurs just before the shift of 'silent' or 'labile' synapses to functional ones [START_REF] Groc | AMPA signalling in nascent glutamatergic synapses: there and not there![END_REF] and glutamate spillover was shown to be critical for the activation of 'silent synapses' [START_REF] Balland | Silent synapses in developing rat nucleus tractus solitarii have AMPA receptors[END_REF]. In agreement with this hypothesis, it was recently shown that GABA A -R and NMDA-R synaptic currents can be recorded prior to AMPA-R EPSCs in the neocortex and jointly contribute to the development of AMPA-R mediated transmission [START_REF] Wang | GABA regulates excitatory synapse formation in the neocortex via NMDA receptor activation[END_REF]. Still, the regulation of AMPA-Rs by NMDA-R-driven ENOs is probably not so straightforward. Indeed, while some reports suggested that NMDA-R signalling early in development negatively regulates the recruitment of functional AMPA-Rs into synapses [START_REF] Hall | Regulation of AMPA receptor recruitment at developing synapses[END_REF], others proposed a positive regulation of AMPA-Rs by NMDA-R-mediated transmission [START_REF] Zhu | Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity[END_REF][START_REF] Shi | Developmental depression of glutamate neurotransmission by chronic low-level activation of NMDA receptors[END_REF][START_REF] Voigt | Activation of early silent synapses by spontaneous synchronous network activity limits the range of neocortical connections[END_REF][START_REF] Brill | Sequential changes in AMPA receptor targeting in the developing neocortical excitatory circuit[END_REF]. In fact, this controversy belongs to a more general one, as other studies have indicated that the maturation of these two types of receptors might be independent [START_REF] Meguro | Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs[END_REF][START_REF] Okabe | Survival and synaptogenesis of hippocampal neurons without NMDA receptor function in culture[END_REF][START_REF] Zhu | Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery[END_REF][START_REF] Colonnese | Chronic NMDA receptor blockade from birth delays the maturation of NMDA currents, but does not affect AMPA/kainate currents[END_REF]. This debate underlies the complex role of NMDA-R signalling during development and makes it difficult to attribute a single function to early NMDA-R-driven oscillations.

The developing neocortex: a network in a 'critical state'? ENO dynamics are characterized by a massive recruitment of neuronal populations throughout cortical subregions irrespective of anatomical boundaries [START_REF] Garaschuk | Large-scale oscillatory calcium waves in the immature cortex[END_REF][START_REF] Adelsberger | Cortical calcium waves in resting newborn mice[END_REF][START_REF] Yang | Three patterns of oscillatory activity differentially synchronize developing neocortical networks in vivo[END_REF]. Interestingly, during a restricted developmental period of 1 or 2 days, these large synchronizations co-exist with local events in the form of GDPs [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. The coexistence of these two network events with very different sizes could be the sign of an 'avalanche' mode of activity in developing neocortical slices [START_REF] Plenz | The organizing principles of neuronal avalanches: cell assemblies in the cortex?[END_REF][START_REF] Werner | Brain dynamics across levels of organization[END_REF]. The term 'neuronal avalanche' was recently introduced to describe the fact that the size of spontaneous neuronal synchronizations can follow a power-law distribution implying that both rare massive events and frequent local ones can occur in the same network [START_REF] Plenz | The organizing principles of neuronal avalanches: cell assemblies in the cortex?[END_REF][START_REF] Werner | Brain dynamics across levels of organization[END_REF]. An avalanche type of organization is the sign of a network in a critical state and was reported in immature organotypic cortical cultures [START_REF] Stewart | Homeostasis of neuronal avalanches during postnatal cortex development in vitro[END_REF].

By definition, a critical state is at the edge of stability, and any small perturbation would break it. Several observations could indeed indicate that network dynamics in the developing neocortex can rapidly switch to a pathological state. Maybe the most striking one is the fact that the neocortex is exceptionally prone to seizures at early developmental stages [START_REF] Holmes | Effects of seizures on developmental processes in the immature brain[END_REF][START_REF] Bender | Epileptogenesis in the developing brain: what can we learn from animal models?[END_REF][START_REF] Holmes | Postnatal concerns in children born to women with epilepsy[END_REF][START_REF] Scantlebury | Age-dependent consequences of status epilepticus: animal models[END_REF]. For example, it was recently shown that GDPs in that region rapidly evolve towards interictal and ictal-like seizures if synaptic activity levels are pharmacologically increased (Rheims et al. 2008b). Likewise, the blockade of excitatory amino acid transporters (EAAT) that remove glutamate from the extracellular space induces an epileptiform 'suppression burst' activity pattern [START_REF] Demarque | Glutamate transporters prevent the generation of seizures in the developing rat neocortex[END_REF]). These slow network oscillations (SNOs) induced by EAAT blockade share striking features with hypoxia-induced-ENOs [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF] regarding their dynamics and mechanisms (Fig. 3). SNOs appear as an amplified form of ENOs in regard to individual event kinetics and network dynamics. Interestingly, hypoxic-ischaemic encephalopathy in human neonates is very often associated with discontinuous EEG patterns including 'suppression bursts' , in which dynamics and suggested cellular mechanisms can also be intriguingly similar to cENOs [START_REF] Biagioni | Constantly discontinuous EEG patterns in full-term neonates with hypoxic-ischaemic encephalopathy[END_REF][START_REF] Ohtahara | Epileptic encephalopathies in early infancy with suppression-burst[END_REF]Milh et al. 2007a). Moreover, hypoxic conditions both facilitate ENOs [START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF] and impair glutamate transporter function [START_REF] Dallas | Hypoxia suppresses glutamate transport in astrocytes[END_REF]. Altogether, this would suggest that ENOs could be a network pattern critically close to a pathological state.

To conclude, we propose a robust sequence for the maturation of coherent activity patterns in cortical structures with the role of NMDA-R driven ENOs remaining an open question. Because of their resemblance to both physiological patterns like stage III retinal waves or neuronal avalanches, and pathological oscillations like the bursts induced by an impairment of EAAT, it is at present difficult to assign a definite developmental function to ENOs. Finding the in vivo electrical pattern corresponding to cENOs is a difficult task. It will require combining multineuron imaging with electro-physiological recordings but it will certainly help to address this issue.

Rosa

  Cossart is currently leading a research group in the Institut de Neurobiologie de la Méditerranée (INSERM U901, Marseille, France). Her research interests focus on the maturation of functional cortical GABAergic microcircuits. She was not initially trained as a neurobiologist but as a physicist with a strong education in mathematics, studying engineering in the Ecole Centrale de Paris. In 2001, she obtained a PhD in biophysics at Paris VI University under the supervision of Dr C. Bernard in the laboratory directed by Dr Yehezkel Ben-Ari. She next pursued her research training as a postdoctoral fellow in Professor Rafael Yuste's laboratory at Columbia University (New York, USA). There she developed a novel approach to study network dynamics in brain slices that combines two-photon calcium imaging with online mathematical analysis and targeted electrophysiological recordings. Since 2002 she has been as a permanent research fellow in the Centre National de la Recherche Scientifique. She received in 2005 a 'Medaille de Bronze' from the CNRS, an award that recognizes her early research achievements.

Figure 3 .

 3 Figure 3. ENOs present striking similarities with both a physiological and a pathological network pattern A, ENO-associated membrane potential depolarisations recorded in current clamp mode before (a) and after (b)decreasing the rate of the perfusion from 4 to 1 ml min -1 (data taken from[START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. Similar effects were found in anoxic/aglycaemic perfusion conditions (see[START_REF] Allene | Sequential generation of two distinct synapse-driven network patterns in developing neocortex[END_REF]. B, comparison between the membrane potential depolarization (top black trace), the calcium fluorescence signal (green) and the spontaneous excitatory postsynaptic currents (sEPSCs, bottom black, V m = -60 mV) associated with the spontaneous ENO illustrated in (Aa) and with a stage III retinal wave (reprinted from[START_REF] Blankenship | Synaptic and extrasynaptic factors governing glutamatergic retinal waves[END_REF] with permission from Elsevier). Note the similarity between the two patterns. C, same as in B but comparing ENOs produced by a mild anoxic condition occurring when decreasing the perfusion rate (Ab) with slow network oscillations (SNOs) induced by pharmacological EEAT blockade with DL-TBOA (unpublished data from L. Aniksztejn & A.A. Cattani).


The maturation of cortical interneuron diversity: how multiple developmental journeys shape the emergence of proper network function

Rosa Cossart

If the classical functional attribute of cortical GABAergic interneurons is to mediate synaptic inhibition in the adult cortex, it is becoming evident that their major task is instead to shape the spatio-temporal dynamics of the network oscillations that support most brain functions. This complex function involves a division of labour between morpho-physiologically diverse interneuron subtypes. Both the central network function and the bewildering heterogeneity of the interneuron population are especially emphasized during cortical development: at early postnatal stages, a single GABAergic neuron can efficiently pace the activity of hundreds of other cells, whereas some interneuron subtypes are still poorly developed. Given the role of coherent activity in brain development, this confers to GABAergic interneurons a major role in the proper maturation of cortical networks.

Introduction

It is now becoming increasingly evident that a selective disruption of cortical GABAergic interneuron development, resulting from either genetic or epigenetic factors, is related to many neurological disorders like epilepsy, mental retardation, autism or even schizophrenia [START_REF] Nosten-Bertrand | Epilepsy in Dcx knockout mice associated with discrete lamination defects and enhanced excitability in the hippocampus[END_REF][START_REF] Kerjan | Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures[END_REF][START_REF] Marsh | Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females[END_REF][START_REF] Yu | Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy[END_REF][START_REF] Cristo | Development of cortical GABAergic circuits and its implications for neurodevelopmental disorders[END_REF][START_REF] Cobos | Mice lacking Dlx1 show subtypespecific loss of interneurons, reduced inhibition and epilepsy[END_REF][START_REF] Lewis | Cortical inhibitory neurons and schizophrenia[END_REF][START_REF] Batista-Brito | Gene expression in cortical interneuron precursors is prescient of their mature function[END_REF]. Interestingly, the developmental loss of restricted interneuron subpopulations [START_REF] Cobos | Mice lacking Dlx1 show subtypespecific loss of interneurons, reduced inhibition and epilepsy[END_REF][START_REF] Batista-Brito | The cell-intrinsic requirement of Sox6 for cortical interneuron development[END_REF] or subtle functional alterations of interneuron physiological properties [START_REF] Yu | Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy[END_REF] were shown to have dramatic consequences often leading to the initiation of seizure activity at early postnatal stages. Since epilepsy can be easily conceived as the direct outcome of an inhibition deficit due to interneuron loss, understanding other more complicated brain disorders certainly indicates more elaborate cellular mechanisms and interpretations.

Two nonexclusive explanations account for the multiple impacts on brain operation of an altered development of GABAergic neurons. First, in addition to providing inhibition, GABAergic interneurons are the substrate of several nonlinear network operations required to support high brain functions. To this aim, GABAergic interneurons come in many flavors, each of them designed to carry a specific circuit task and bear the variety of network oscillations generated by mature cortical networks [START_REF] Klausberger | Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations[END_REF]. The second explanation for the multiple consequences of an abnormal maturation of subpopulations of GABAergic cells is that aberrant development is not restricted to the affected microcircuits but rather affects the entire network. Indeed, during brain development, there is an almost continuous crosstalk between GABAergic interneurons and the networks they integrate into, whereby the same population that supports adult network function also controls the generation of early network patterns which in turn contribute to network development creating a feedback loop.

Until recently, investigating the functional maturation of GABAergic microcircuits was seriously hampered for one major reason: developing interneuron subtypes cannot be readily identified and classified as they have not yet reached their mature neurochemical and morpho-physiological attributes (Figure 1). The advance in novel imaging and genetic strategies to dissect the functional organization of developing GABAergic neurons has opened a new era for the investigation of GABA neuron development. We will review recent work aiming at understanding how the functional diversity of this major neuronal population develops in parallel with the maturation of coherent network patterns.

Interneurons have a crucial early network function that spans throughout an extended developmental period

At adult stages it is now well established that the major function of cortical GABAergic interneurons is to organize in time and space the generation of most network oscillations associated with behavioural and cognitive brain functions [10,11 ,12 ]. This central network function of the GABAergic interneuron population is emphasized during cortical development in several ways. First, the interneuron population pioneers cortical development, as the peak of genesis for GABAergic cells takes place a couple of days before that of their glutamatergic counterparts in rodents [START_REF] Danglot | The development of hippocampal interneurons in rodents[END_REF]. Cortical GABAergic neurons, at least in nonprimate vertebrates, are generated in the subpallium, mainly from two transient structures, the medial and caudal ganglionic eminences [START_REF] Anderson | Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes[END_REF][START_REF] Batista-Brito | The developmental integration of cortical interneurons into a functional network[END_REF][START_REF] Marin | A long, remarkable journey: tangential migration in the telencephalon[END_REF] but also from the preoptic area [START_REF] Gelman | The embryonic preoptic area is a novel source of cortical GABAergic interneurons[END_REF]. Among them, some GABAergic neurons are postmitotic and start migrating tangentially towards the cortex as early as embryonic day 10 [START_REF] Danglot | The development of hippocampal interneurons in rodents[END_REF][START_REF] Miyoshi | Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors[END_REF]. Probably mostly because they constitute an older cell population, the morpho-physiological properties and firing activity of interneurons are globally more developed than those of glutamatergic cells within the same network during each stage of development. Hence the GABAergic network is already operative in utero in the CA1 hippo-campal region at a time when glutamatergic cells are poorly developed morphologically and barely receive any synaptic input [19 ,20]. Regarding the maturation of their intrinsic excitability, it was recently shown that neocortical interneurons display a lower threshold for action potential generation than pyramidal cells at early postnatal stages [START_REF] Rheims | Excitatory GABA in rodent developing neocortex in vitro[END_REF] which confers them a higher probability to be recruited at the early phases of network synchronization [START_REF] Rheims | Layer-specific generation and propagation of seizures in slices of developing neocortex: role of excitatory GABAergic synapses[END_REF]. Interestingly, the firing of immature hippocampal interneurons was also shown to be maintained at a high rate through specific regulatory mechanisms [START_REF] Segerstrale | High firing rate of neonatal hippocampal interneurons is caused by attenuation of afterhyperpolarizing potassium currents by tonically active kainate receptors[END_REF]. On the postsynaptic side, cortical GABAergic synapses mature on average before glutamatergic ones in most cell types ranging from pyramidal neurons and interneurons [19 ,24,25 ] to oligodendrocyte precursors [START_REF] Velez-Fort | Postnatal switch from synaptic to extrasynaptic transmission between interneurons and NG2 cells[END_REF], indicating a very general sequence

Immature stage

Adult stage

Bewildering diversity of the developing interneuron population. Schematic comparison between an immature developmental stage (left) for cortical interneuron networks (i.e. around birth in the rodent hippocampus) and the adult stage (right). At early stages of development, the developing interneuron network comprises (i) well-developed interneurons almost already displaying their adult morphological and neurochemical features (blue); (ii) interneurons with developed anatomical features but that do not express yet their characteristic neurochemical properties (gray future pink cell); (iii) neurochemically and morphologically immature interneurons. Interneurons that belong to the same family (like pink cells) may develop differently. Well developed interneurons already receive both GABAergic and glutamatergic inputs (GG-interneurons) whereas poorly developed cells are still not innervated as illustrated in the panels below taken with permission from [START_REF] Hennou | Early sequential formation of functional GABA(A) and glutamatergic synapses on CA1 interneurons of the rat foetal hippocampus[END_REF]. Note that none of the reconstructed interneurons filled at P0 displays a recognizable morphology as compared to interneurons in the adult hippocampus (right panel) where different interneuron subtypes can be easily for the maturation of receptors. Given that this developmental sequence also holds for newborn neurons maturing in an adult environment [START_REF] Markwardt | Inputspecific GABAergic signaling to newborn neurons in adult dentate gyrus[END_REF], it likely reveals a mostly cell autonomous intrinsic sequence for receptor maturation. Along these lines, a direct inductive action of GABAergic transmission on AMPA-receptor development was recently demonstrated [25 ,28,29] Pfeffer, 2009 15126/id. However, it is important to stress that a differential maturation of GABAergic synapses is likely to occur along the somato-dendritic domain with probably a delayed development of somatic GABAergic synapses [START_REF] Tyzio | The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite[END_REF][START_REF] Chattopadhyaya | GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex[END_REF][START_REF] Fiorentino | GABA(B) receptor activation triggers BDNF release and promotes the maturation of GABAergic synapses[END_REF][START_REF] Marty | Postnatal maturation of Na + , K + , 2Cl S cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: an immunocytochemical analysis[END_REF]. Therefore at least part of the GABAergic interneuron network starts operating a couple of days before the glutamatergic one, conferring a crucial network function to the interneuron population. Nevertheless, it is important to temper this statement by taking into account interneuron diversity since it is very likely that only specific subtypes of cortical GABAergic interneurons display an early functional maturation endowing them network function (see below).

The second major support for a key early network function of the developing interneuron population stems from the fact that GABAergic transmission depolarizes and excites neurons at early developmental stages due to a higher intracellular chloride content. Obviously, within a given developing structure, some neurons may be excited while others inhibited by GABAergic transmission depending on their intrinsic chloride load, as supported by the heterogeneity of intracellular chloride concentrations observed using chloride imaging techniques [START_REF] Glykys | Differences in cortical versus subcortical GABAergic signaling: a candidate mechanism of electroclinical uncoupling of neonatal seizures[END_REF]. This observation is a very robust phenomenon observed throughout developing structures and species, resulting from a delayed maturation of chloride extruding transporters compared to importers [START_REF] Ben-Ari | GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations[END_REF].

Regarding depolarizing GABA actions it is important again to consider the developmental and morpho-physiological complexities of the interneuron population (Figure 1). First, the action of GABAergic transmission on a given pyramidal neuron is very likely to be highly dependent not only on the age of the postsynaptic neuron, but also on the type of presynaptic interneuron, even at nearby synapses [START_REF] Foldy | Regulation of fast-spiking basket cell synapses by the chloride channel ClC-2[END_REF][START_REF] Szabadics | Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits[END_REF][START_REF] Woodruff | Depolarizing effect of neocortical chandelier neurons[END_REF]. Also, in agreement with an advanced stage of maturation, it is possible that older interneurons display a lower intracellular chloride concentration than pyramidal cells resulting in hyperpolar-izing GABAergic inputs [START_REF] Banke | GABAergic input onto CA3 hippocampal interneurons remains shunting throughout development[END_REF] while younger interneurons will still be depolarized by GABAergic transmission [39 ,40]. This probably stems from the general increased expression of the chloride exporter KCC2 as a function of age in interneurons [41 ]. Particular interneuron subtypes, like NPY hilar interneurons, may even display a specific chloride homeostasis that further extends into adulthood [42].

A firm evidence in support of a central role of specific GABAergic microcircuits in synchronizing early neuronal activity is the recent finding that a few exceptional interneurons act as network 'hubs' that is high connectivity nodes gating information flow, through a dense axonal arborisation (Figure 2) and high intrinsic and synaptic excitabilities [43 ]. Modifying the activity of a single hub neuron can synchronize (Figure 2) or desynchronize network dynamics depending on the type of hub neuron and on the state of the network. This indicates that the network function of hub neurons relies on a more complex chain of neuronal activation than a mere direct excitatory action of GABA. In fact, it remains to be determined whether excitatory GABAergic transmission is indeed a mandatory condition to hub function.

We have reviewed recent data indicating that the early maturation of GABAergic networks will endow some interneurons a unique early network function hence electing them as major contributors to activity-dependent development processes. However, it is probably equally important to stress that a reason for the particular susceptibility of the interneuron population to developmental insults, linking them to many brain disorders, is the long time span of interneuron development from in utero stages to puberty. Until when do interneurons continue developing? The critical period for GABAergic neuron maturation extends towards late postnatal stages in rodents maybe even after the stabilization of glutamatergic networks [44]. Hence, the electrophysiological properties of fast-spiking cortical interneurons develop until 40 postnatal days ([45 ,46] and Figure 2) while on the postsynaptic side, the structural and functional determinants of GABAergic synaptic transmission continue developing for similar time periods [47,48 ,49]. The continuous postnatal maturation of part of GABAergic networks may explain the late postnatal emergence of address the development of precisely defined morphophysiologically interneuron families. However, this is now possible using 'genetic fate mapping' approaches.

As other developmental processes, the maturation of GABAergic functional microcircuits results from the interplay between intrinsic genetic programs and neuronal activity. Recent studies clearly indicate that the morpho-physiological identity of GABA neurons is strongly predetermined by their embryonic origin [15,18 ,60 ,61-65]. In other words, the adult phenotype of a given interneuron is largely dependent on where and when in the ganglionic eminences it was born (Figure 2). Hence, the cortical interneuron subtypes arising from the MGE and CGE are different [60 ,61,66], the MGE producing mostly the parvalbumin-containing and somatostatin-containing neocortical interneurons while the CGE gives rise to calretinin-expressing and VIPexpressing cells [15,18 ,60 ,63]. It was also recently shown that two considered distinct hippocampal interneuron subtypes, Ivy and nitric oxide synthase positive neurogliaform cells are both derived from MGE progenitors under the control of Nkx2-1 [START_REF] Tricoire | Common origins of hippocampal Ivy and nitric oxide synthase expressing neurogliaform cells[END_REF]. The strong embryonic predetermination of cortical interneuron identity carries implications that extend beyond the mere genetic analysis of interneuron development. Indeed, it can be applied as a tool to study different interneuron subtypes at an immature stage when they do not appear morpho-physiologically and neurochemically different yet using inducible genetic fate-mapping approaches [START_REF] Miyoshi | Directing neuron-specific transgene expression in the mouse CNS[END_REF]. Moreover, this spatio-temporal embryonic stamp is so robust that it could almost be proposed as a complementary way to reach a compelling classification of adult interneuron types, an even now problematic issue [START_REF] Ascoli | Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex[END_REF].

When and how activity may influence interneuron maturation

If interneuron diversity is largely predetermined by genetic programs, it is also well established that activity and environmental factors are equally important at every step of interneuron development, from early migration [69 ,70], postnatal cortical layer sorting [41 ], to late network integration [START_REF] Chattopadhyaya | GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex[END_REF]41 ]. Developing interneurons are particularly well designed to be directly influenced by activity. Hence, it was recently shown that actionpotential-independent release of GABA originating from developing cerebellar interneurons could be sensed by the presynaptic cells themselves in the form of 'preminis'

[71], thus providing developing interneurons with a feedback 'private' source of GABA possibly serving their own maturation [START_REF] Chattopadhyaya | GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex[END_REF]. In addition, as discussed above, the development of cortical GABAergic microcircuits is a prolonged process, extending well into the postnatal period in rodents, a time window more likely to involve action-potential-dependent-neuronal activity. Indeed, the earliest forms of network electrical activity patterns appear postnatally in rodents [72,73 ]. Accordingly, it was adult patterns of network dynamics [START_REF] Colonnese | A conserved switch in sensory processing prepares developing neocortex for vision[END_REF][START_REF] Rochefort | Sparsification of neuronal activity in the visual cortex at eye-opening[END_REF] given the major contribution of GABAergic inputs in the emergence of sparse network spikes [START_REF] Wolfe | Sparse and powerful cortical spikes[END_REF]. It also explains why some interneuron subtypes are particularly prone to postnatal environmental insults (see below). In fact, it may even well be that specific interneuron populations continue being generated throughout adulthood since the SVZ was shown to continue producing GABAergic interneurons postnatally [START_REF] Inta | Neurogenesis and widespread forebrain migration of distinct GABAergic neurons from the postnatal subventricular zone[END_REF].

The strong genetic predetermination of interneuron subtypes facilitates interneuron developmental studies

Given the major role of GABAergic networks in cortical development it is surprising that the morpho-physiological development of different GABAergic microcircuits as well as the emergence of their respective network function remains largely unknown. This is because the organization of the GABA neuron population is complex and even more difficult to study during development than adulthood (Figure 1). As extensively commented before [START_REF] Mcbain | Interneurons unbound[END_REF], the connectivity of GABAergic microcircuits is amazingly organized. Although heterogeneous and complex, a general wiring diagram for adult cortical GABAergic networks can now be pictured as a result of a combined effort of several groups worldwide [START_REF] Klausberger | Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations[END_REF].

The description of similar functional connectivity maps in immature GABAergic microcircuits was until recently almost impossible because developing interneurons have not yet acquired the characteristic adult features used to classify them [START_REF] Ascoli | Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex[END_REF](Figure 1); and they display an heterogeneous development as discussed above. One possible way to challenge this limitation is to use imaging approaches to map functional connectivity patterns [START_REF] Woodruff | Depolarizing effect of neocortical chandelier neurons[END_REF][START_REF] Luo | Genetic dissection of neural circuits[END_REF][START_REF] Marshel | Targeting single neuronal networks for gene expression and cell labeling in vivo[END_REF][START_REF] Scanziani | Electrophysiology in the age of light[END_REF]. Using a pairwise description of multineuron calcium activity combined to electrophysiology to reconstruct online the connectivity of developing hippocampal networks in mice where GABAergic neurons were GFPlabelled, the functional organization of the developing hippocampus was recently described [43 ]. It was shown that the early postnatal CA3 region of the hippocampus displayed a scale-free mode of organization that is that the distribution of connections between neurons followed a power law [START_REF] Boccaletti | Complex networks: structure and dynamics[END_REF] where 'hub' neurons were GABAergic interneurons displaying a widespread axonal arborisation, on average four times longer than the axonal length of other interneurons in the developing CA3 region of the hippocampus (Figure 2). It is important to stress how concepts from graph theory and statistical physics provide several useful models for the interpretation of imaging data to study the organization of complex dynamical systems such as developing neuronal networks. Still, if imaging approaches allow studying the general functional connectivity of developing GABAergic microcircuits without any a priori assumption regarding the importance of a particular interneuron subtype, they cannot easily recently shown that early environmental stimulation accelerates the postnatal development of GABAergic neurotransmission and in particular the developmental decrease of intracellular chloride concentration [74 ].

What type of activity may mostly contribute to GABAergic interneuron development? Activity in developing neurons is usually correlated between cells, in the form of spontaneous and recurrent calcium rises [75,76]. As reviewed elsewhere [76], a bewildering diversity of network dynamics and mechanisms have been described so far in developing neuronal structures. One possible way to simplify the picture is to classify early synchronous activity patterns according to the developmental stage at which they dominate cortical networks. Indeed, the maturation of coordinated activity patterns appears to follow a precise and coordinated developmental sequence, common to many developing structures. Hence, in both the hippocampus [73 ] and neocortex [77], correlated neuronal activity emerges around birth. It first synchronizes restricted gap-junction-coupled neuronal assemblies producing membrane potential oscillations associated with long-lasting calcium plateaus (Synchronous Plateau Assemblies -SPAs). Later, it involves large neuronal populations synchronized by synaptic transmission (Giant Depolarizing Potentials -GDPs; Figure 2). Given their specific spatial dynamics and associated calcium plateaus, SPAs could be proposed as playing a role in the consolidation of functional GABAergic microcircuits. Several observations indeed suggest that sustained elevations of intracellular calcium concentration encode a specific trigger signal to pathways regulating gene transcription [78 ].

Given its postnatal emergence, electrical activity is certainly more likely to influence the development of latedeveloping rather than early-developing interneurons [41 ,79]. This may explain why the late maturing [START_REF] Gozlan | Interneurons are the source and the targets of the first synapses formed in the rat developing hippocampal circuit[END_REF][START_REF] Tyzio | The establishment of GABAergic and glutamatergic synapses on CA1 pyramidal neurons is sequential and correlates with the development of the apical dendrite[END_REF]45 ], parvalbumin-containing perisomatic targeting interneurons are frequently pointed out in numerous developmental disorders [5,9,48 ,80,81].

Conclusion

A new era for interneuron developmental studies has recently opened thanks to the combination of novel genetic and imaging approaches as well as to the increasing evidence that interneuron diversity may be embryonically predetermined. It is now possible to foresee interneuron diversity even at the earliest stages of cortical development. Developing interneurons support network function, maybe even more stronger than in adulthood.

Their engagement in early network patterns is the seed for a proper development of cortical networks. But interneurons do not mature as a uniform unit; diversity also prevails upon their developmental journey. Hence the early maturation of some interneuron subtypes will endow them a crucial role in activity-dependent processes while the late maturation of others could confer them with a particular susceptibility to environmental and activity-dependent insults. Along these lines, it may well be that GABAergic hub neurons are born earlier than other interneuron subtypes, a hypothesis that could be addressed using fate-mapping approaches. A better understanding of interneuron functional diversity will certainly help the interpretation of their various maturation patterns. In any case, the diverse and long developmental journey of cortical interneurons largely explains the intimate links between determinants of GABA neuron proper development and brain disorders.

A developmental analysis of the depolarizing actions of GABA, from birth to 30 postnatal days, using non-invasive, somatic cell-attached recordings of GABA(A) and NMDA channels to monitor the GABA driving force and resting membrane potential respectively. The GABA driving force is found to be strongly depolarizing in most pyramidal neurons and interneurons during the first postnatal week in vitro as well as in vivo. A study showing that Lhx6-interneurons migrating in cultures of cortical neurons change their responsiveness to GABA from a motogenic to a stop signal when GABA actions switch from depolarizing to hyperpolarizing after the developmental upregulation of the potassium-chloride cotransporter KCC2.

40

Figure 1

 1 Figure 1

  identified and classified according to their axonal arborisation (taken with permission from Cossart et al. Hippocampus 2006).

  Figure 2

(Figure 2

 2 Legend) The long developmental journey of cortical GABAergic interneurons. (1) Schematic representation of different steps in the development of cortical GABAergic neurons from embryonic to adult stages. Top panel: Perinatal development from late embryonic to early postnatal stages. Left: Interneuron phenotypes are largely predetermined by their spatial and temporal embryonic origins with somatostatin (SOM) and parvalbumin (PV)-expressing cells mostly originating from the medial ganglionic eminences (MGE) whereas VIP, calretinin and Reelin-containing neurons are preferentially born in the caudal ganglionic eminences (CGE) as established in[START_REF] Miyoshi | Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors[END_REF][START_REF] Miyoshi | Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons[END_REF]. Right: Coherent network activity patterns emerge around birth and interneurons are central for the synchronization of neuronal activity. For example stimulation of hub GABA neurons, with a widespread axonal morphology (red) as compared to other interneurons at the same developmental stage (blue), synchronizes the activity of hundreds of cells as shown in the rasterplot below (adapted with permission from [43]). Bottom panel: Postnatal development of interneurons. Left: The morphophysiological properties of dentate gyrus basket-cells continue developing at late postnatal stages (taken with permission from [45]). Right: Schematic representation showing that in adult networks, different types of interneurons are differentially involved in the generation of network oscillations like gamma or theta rhythms.

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Acknowledgements

I thank all the 'Cossart team' members for helpful discussions and suggestions. I thank the FP7-ERC 'GABA Networks' grant (# 242842), the Fondation pour la Recherche Medicale, The Bettencourt-Schueller Foundation, the CNRS and the INSERM for financial support.