A Chlorzoxazone

Channel Bkca

RESCUES Agonist

Marion Piquemal

Noura Abdulkarim-Abdalla

Paula Ortiz-Romero

Valerie Lemaire-Mayo

Wim E Crusio

Eric Louette

Victoria Campuzano
email: vcampuzanou@ub.edu

Susanna Pietropaolo
email: susanna.pietropaolo@u-bordeaux.fr

THE PATHOLOGICAL PHENOTYPES OF WILLIAMS-BEUREN SYNDROME IN A PRECLINICAL MODEL

Williams-Beuren syndrome (WBS) is a rare developmental disorder caused by the deletion of a 1.5 Mb region in chromosome 7 (7q11.23). WBS has been recently modelled by a mutant mouse line having a complete deletion (CD) of the equivalent locus on mouse chromosome 5, thus resembling the genetic defect found in WBS patients. CD mice have been shown to have physical and neurobehavioral abnormalities that recapitulate most of the symptoms associated with human WBS, including cardiovascular, motor, social, emotional and sensory alterations. This model has been largely used to investigate the etiopathological mechanisms of WBS; nonetheless, pharmacological therapies for this syndrome have not been identified yet. Here we propose a novel treatment for WBS, chlorzoxazone (CHLOR), i.e., a molecule targeting calcium-activated large conductance potassium (BKCa) channels, since a reduction in the expression of these channels has been recently described in neurons from WBS patients, as well as in other rare developmental pathologies. Our results demonstrate both the acute and chronic effects of CHLOR on some major pathological phenotypes of CD mice, including several behavioural alterations and cardiac hypertrophy. We conclude that BKCa channels are a therapeutic target of high potential for clinical applications and are likely to play a key role in the etiopathology of WBS.

INTRODUCTION

Williams-Beuren syndrome (WBS) is a rare developmental disorder, caused by the hemizygous deletion of 26-28 contiguous genes on chromosome band 7q11.23 [START_REF] Schubert | The genomic basis of the Williams-Beuren syndrome[END_REF]. WBS patients present specific physical abnormalities, including craniofacial alterations and growth retardation, together with cardiovascular anomalies, including a generalized arteriopathy with aortic stenosis and hypertension, and cardiac hypertrophy [START_REF] Pober | Williams-Beuren syndrome[END_REF]. Patients also show elevated anxiety levels, acoustic and sensory alterations, hypotonia and motor problems, and a characteristic cognitive profile including hypersociability and deficient visuospatial abilities [START_REF] Martens | Research Review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype[END_REF].

Recently, a mouse model recapitulating the complete chromosomic deletion (CD mouse) and most of the cardio-vascular and neurobehavioural phenotypes of WBS has been engineered [START_REF] Segura-Puimedon | Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder[END_REF]. This pre-clinical model has largely contributed to advance our understanding of the molecular pathological mechanisms involved in WBS [START_REF] Borralleras | Intracisternal Gtf2i Gene Therapy Ameliorates Deficits in Cognition and Synaptic Plasticity of a Mouse Model of Williams-Beuren Syndrome[END_REF][START_REF] Borralleras | Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome[END_REF][START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF][START_REF] Dasilva | Altered Neocortical Dynamics in a Mouse Model of Williams-Beuren Syndrome[END_REF][START_REF] Jimenez-Altayo | Stenosis coexists with compromised alpha1-adrenergic contractions in the ascending aorta of a mouse model of Williams-Beuren syndrome[END_REF], including reduced brain development, altered synaptic mechanisms and morphological abnormalities in specific brain areas. The CD model has also been recently employed to test the efficacy of potential novel therapeutic approaches to WBS, especially focusing on non-pharmacological interventions [e.g., based on natural polyphenolic extracts, (Ortiz-Romero, [START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF]]. Nonetheless, effective pharmacological treatments acting on both the behavioural and the cardiovascular phenotypes of WBS patients are still lacking, thus highlighting an urgent need of identifying novel powerful therapeutic targets. Potassium (K+) channels are of high interest for the functionality of the nervous system, as they play a crucial role in regulating the triggering of neurons and the release of neurotransmitters [START_REF] Latorre | Large conductance Ca2+-activated K+ (BK) channel: activation by Ca2+ and voltage[END_REF]. This modulation of synaptic transmission and electrical discharge at the cellular level is due in particular to the expression of large-conductance Ca2+-activated K+ (BKCa) channels [START_REF] Sah | Channels underlying neuronal calcium-activated potassium currents[END_REF]. The opening of these channels causes a movement towards the potassium equilibrium potential and thus accelerates the repolarization of the action potentials, allowing faster stimulation [START_REF] Hu | Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release[END_REF]). In addition, BKCa channels modulate the activity of dendrites as well as astrocytes and microglia. Beside their role in the central nervous system, BKCa channels are also involved in smooth muscle contraction and endocrine cell secretion [START_REF] Jackson | Potassium channels in the peripheral microcirculation[END_REF][START_REF] Tykocki | Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles[END_REF]. These channels are assembled as hetero-octamers of four α-subunits (KCNMA1 protein) and four auxiliary regulatory β-subunits, and are activated by membrane depolarization and increased intracellular Ca2+ concentration [START_REF] Gribkoff | Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium[END_REF]. Converging lines of evidence support the role of BKCa channels in the etiopathology of several neurodevelopmental disorders (NDDs) [START_REF] Lee | Fragile X syndrome: mechanistic insights and therapeutic avenues regarding the role of potassium channels[END_REF]. A KCNMA1 gene disruption was described in a subject with autism, associated with a functional defect of BKCa channels [START_REF] Laumonnier | Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation[END_REF]. We also demonstrated a reduced expression of the KCNMA1 protein in another rare NDD, i.e., Fragile X syndrome (FXS), both in patients and in the related Fmr1-KO mouse model [START_REF] Hebert | Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule[END_REF], together with a reduced functionality of brain BKCa channels [START_REF] Zhang | Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice[END_REF]. Recently, reduced expression of KCNMA1 has been reported in neurons from WBS patients [START_REF] Khattak | Human induced pluripotent stem cell derived neurons as a model for Williams-Beuren syndrome[END_REF]. These data strongly support the relevance of BKCa channels as a potential therapeutic target common to multiple NDDs (N'Gouemo 2014), suggesting that these disorders should be considered as "channelopathies" [START_REF] Bailey | KCNMA1-linked channelopathy[END_REF]. Preclinical studies have indeed demonstrated that the administration of molecules acting as BKCa channel openers may rescue the brain and behavioural abnormalities of Fmr1-KO mice [START_REF] Hebert | Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule[END_REF][START_REF] Zhang | Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice[END_REF][START_REF] Carreno-Munoz | Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome[END_REF]. Nonetheless, the relevance of BKCa channels as therapeutic targets for WBS has never been specifically addressed so far. Hence, here we evaluated whether the administration of one molecule acting on BKCa channels could represent an effective pharmacological strategy to treat WBS symptoms, including behavioural, physical, brain and cardiovascular alterations. To this end we focused on Chlorzoxazone, (5-chloro-2,3-dihydro-1,3-benzoxazol-2-one; CHLOR), as we have recently demonstrated the efficacy of this agonist of BKCa channels [START_REF] Liu | Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on large conductance calcium-activated potassium channels in pituitary GH3 cells[END_REF] in the Fmr1-KO mouse model of FXS [START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]. CHLOR is a classical drug, approved from FDA as a muscle relaxant [START_REF] Hohmann | Simultaneous phenotyping of CYP2E1 and CYP3A using oral chlorzoxazone and midazolam microdoses[END_REF], acting on the spinal cord and subcortical areas of the brain [START_REF] Martindale | the Extra Pharmacopoeia[END_REF]. Hence, the main advantage of CHLOR is that it could be rapidly employed in clinical trials through a drug repurposing strategy. In fact, recent pre-clinical studies have highlighted the emerging potential role of CHLOR in healthcare, demonstrating its immunomodulatory [START_REF] Deng | Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation[END_REF]) and neuroprotective properties [START_REF] Bai | Chlorzoxazone exhibits neuroprotection against Alzheimer's disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo[END_REF]. The present study provides with the first characterization of the therapeutic effects of CHLOR administration in the CD mouse model of WBS. To this end, we assessed both acute and chronic effects on the WBS-like behavioural alterations of CD mice, including motor, social, emotional and sensory deficits. Furthermore, we evaluated the effects of chronic treatment with CHLOR on the physical, brain and cardiovascular abnormalities of CD mice. METHODS Animals Subjects were adult (4-5 months old) CD mutant heterozygous mice and their wild-type littermates (maintained on B6 background). Males were more extensively tested, as they are preferentially employed in studies on mouse models of NDDs, including our previous work with CHLOR on the Fmr1-KO model of FXS [START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]. Nonetheless, since WBS affects individuals of both sexes, we replicated part of the experiments in female mice, as described in the Supplementary material section. Mice tested in studies 1 and 2 were bred in our animal facility of Bordeaux University, from CD breeders, heterozygous for the CD mutation [START_REF] Segura-Puimedon | Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder[END_REF]. Breeding trios were formed by mating two heterozygous CD males with a wild-type C57BL/6J female purchased from Janvier (Le Genest St Isle, France). After 2 weeks the sire was removed and the females were single caged and left undisturbed until weaning of the pups. Mice were weaned at 21 days of age and group-housed with their same-sex littermates (3-5 animals/cage). On the same day, tail samples were collected for DNA extraction and subsequent PCR assessment of the genotypes as previously described [START_REF] Segura-Puimedon | Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder[END_REF]. Only litters including males of both genotypes (WT and CD) were used for experiments. Mice used in study 3 were bred and maintained in the animal facility at the University of Barcelona; CD heterozygous mice, obtained as previously described (Segura-Puimedon, Sahun et al. 2014), were crossed with Thy1-YFP transgenic mice (B6.Cg-Tg(Thy1-YFPH)2Jrs/J, Jackson Laboratory) [START_REF] Feng | Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP[END_REF] in order to label pyramidal neurons and allow direct evaluation of dendritic length. CD1 female mice (12±1 weeks old) purchased from Janvier (Le Genest St Isle, France) were used as social stimuli during the social interaction test. This strain has been selected since it was previously largely employed as social stimuli in several social studies from our group, including those on Fmr1-KO mice [START_REF] Pietropaolo | Geneticbackground modulation of core and variable autistic-like symptoms in FMR1 knock-out mice[END_REF][START_REF] Pietropaolo | Dietary supplementation of omega-3 fatty acids rescues fragile X phenotypes in Fmr1-Ko mice[END_REF][START_REF] Oddi | Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome[END_REF], because of its high sociability levels [START_REF] Moles | Ultrasonic vocalization by female mice in the presence of a conspecific carrying food cues[END_REF]. Mice were group-housed (4-5 animals/ cage) and left undisturbed upon arrival at least one week before the social interaction test. All animals were housed in polycarbonate standard cages (33x15x14 cm in size; Tecniplast, Limonest, France), provided with litter (SAFE, Augy, France) and a stainless steel wired lid, and enriched with a cotton nestlet. Food (SAFE, Augy, France) and water were provided ad libitum. The animals were maintained in a temperature (22°C) and humidity (55%) controlled vivarium, under a 12:12 hr light-dark cycle (lights on at 7 a.m.). All experimental procedures were in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and local French and Spanish legislation.

Behavioural tests: To evaluate the therapeutic potential of CHLOR we have chosen behavioural tests that have revealed altered phenotypes in CD mice based on previous data from Dr.

Campuzano's team and from our pilot studies. These phenotypes include motor coordination deficits (rotarod test), hypo-activity (the open field test), hyper-sociability (the direct social interaction test for social habituation), altered natural occurring behaviours (test for nesting abilities in a novel environment and marble burying test), increased anxiety (self-grooming in a novel environment) and alterations in sensory responsiveness (acoustic startle test). The choice of these tests was based on their ability to reveal WBS-like phenotypes in CD mice, and to be sensitive to the therapeutic effects of the molecule CHLOR in a mouse model of another neurodevelopmental disorder, i.e., the Fmr1-KO model for FXS [START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]. Furthermore, these tests were selected since they allow a rapid assessment of mouse behavior, with minimal manipulation of the subjects, thus allowing quick and repeated testing of the same batch of mice, concomitantly reducing the number of subjects needed. All behavioral tests (except nest building assessment) were carried out during the light phase of the cycle. Mice were habituated to the experimental room prior to all behavioral tests, being individually housed in standard polycarbonate cages provided with sawdust, food, and water bottles and left undisturbed for at least 10-15 min before testing began.

Rotarod test: An electrical accelerating rotarod for mice (Model 7650; Ugo Basile, Stoelting, Wood Dale, IL) was used to evaluate motor coordination. Mice were placed on the rotating drum at the baseline speed of 4 rpm. During the 5-min observation period, the speed of rotation increased linearly to 40 rpm. Mice were given three trials, with an intertrial interval of one hour. Each trial ended when the mouse fell from the apparatus or when 5 min had elapsed. The latency to fall from the rotating drum was recorded, averaged across trials and ln-transformed to better conform to the assumptions of parametric ANOVA.. Open field test: This test is used to assess locomotor activity and exploration in laboratory mice [START_REF] Belzung | Rodent models for autism. a critical review[END_REF]. The apparatus consisted of 4 white opaque plastic arenas (42x26x15cm). Each mouse was placed in the center of the arena and left free to explore it for 5 minutes. Automated Tracking of the videos obtained from a camera above the open field was performed with Ethovision (version 11, Noldus Technology, Wageningen, Netherlands) to analyze the total distance travelled.

Direct social interaction test and self-grooming assessment: Social interaction was assessed in a 30x15x14 cm cage, covered by a flat metal grid and with approximately 3 cm of sawdust on the floor, where testing subjects were previously isolated for one hour. During the first 10 min of isolation in the novel cage, behaviour of the subject was videorecorded and the time spent performing self-grooming was afterwards assessed with Observer XT (version 7, Noldus, The Netherlands). An unfamiliar CD1 stimulus female (3 months-old), was then introduced into the testing cage and left there for 6 min. Stimulus females were housed in unisexual groups in a female-only animal room and were in the non-estrous phase when tested (as assessed by the analysis of vaginal smears on testing day). Testing sessions were recorded and videos analyzed with Observer XT (version 7, Noldus, The Netherlands). Affiliative behaviors only of the testing subject were evaluated, including sniffing the head and the snout of the partner, its anogenital region, or any other part of the body; allogrooming (grooming the partner) and traversing the partner's body by crawling over/under from one side to the other. Social habituation was assessed through the analysis of the time spent in affiliative behaviours across 2-min bins.

Nest-building behaviour in a novel environment: The apparatus consisted of an unfamiliar Plexiglas cage (30x15x14 cm), covered by a flat metal grid, with approximately 3 cm of sawdust on the floor, provided with food and a water bottle. Mice were singly placed in the apparatus in the presence of nesting material (one Nestlet, 2.7 g, 2.5 × 2.5 cm and 5mm thick compressed cotton; identical to the material provided in the home cage) and left undisturbed overnight. Nest building scoring was performed by a trained experimenter blinded to the genotype and treatment of the animals, using the following standardized scoring scale [START_REF] Halene | Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia[END_REF][START_REF] Mo | Novel ethological endophenotypes in a transgenic mouse model of Huntington's disease[END_REF][START_REF] Carreno-Munoz | Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome[END_REF]): 1: Nestlet not noticeably shredded; 2: Nestlet 10 to 50% shredded, not used as a nest; 3: Nestlet shredded 50 to 90%, but the shredded material remains scattered in the cage and is not used as a nest; 4: Nestlet shredded >90%, and shredded material used as a flat nest; and 5: Nestlet shredded >90% and used as a rounded nest with sides covering the mouse.

Marble burying: The test was conducted in a polycarbonate rat cage filled with bedding to a depth of 5cm and lightly tamped down. A regular pattern of 20 glass marbles (five rows of four each) was placed on the surface of the bedding prior to each test. An animal was individually placed in the testing cage for 20 min and the number of buried marbles (>2/3 marble covered) was counted.

Acoustic startle test: The apparatus consisted of four acoustic startle chambers for mice (SR-LAB, San Diego Instruments, San Diego, CA, USA). Each comprised a nonrestrictive cylindrical enclosure made of clear Plexiglas attached horizontally on a mobile platform, which was in turn resting on a solid base inside a sound-attenuated isolation cubicle. A high-frequency loudspeaker mounted directly above the animal enclosure inside each cubicle produced a continuous background noise of 65/ 66 dBA and various acoustic stimuli in the form of white noise. Vibrations of the Plexiglas enclosure caused by the whole-body startle response of the animal were converted into analog signals by a piezoelectric unit attached to the platform. These signals were digitized and stored by a computer. The sensitivity of the stabilimeter was routinely calibrated to ensure consistency between chambers and across sessions. A session began when the animals were placed into the Plexiglas enclosure (to which they were habituated for 5 min in the absence of acoustic stimuli the day before the test, in order to minimize the stress). We used two protocols to evaluate acoustic startle test in our CD mice. First, we performed the test with a protocol involving low intensity stimuli that has been used so far only in Fmr1-KO mice where it has allowed detecting the sensory-hyper responsiveness of these FX mice [START_REF] Michalon | Chronic metabotropic glutamate receptor 5 inhibition corrects local alterations of brain activity and improves cognitive performance in fragile X mice[END_REF][START_REF] Zhang | Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice[END_REF][START_REF] Gaudissard | Behavioral abnormalities in the Fmr1-KO2 mouse model of fragile X syndrome: The relevance of early life phases[END_REF]. After 5 min of habituation, mice were presented with pulses of white sound of 20 ms duration and varying intensity: +6, +12 +18 and +24 dB over the 66db background level (namely 72, 78, 84 and 90 dB). Each intensity was presented 8 times, in a randomized order with variable intervals (10 sec to 20 sec) between the onset of each pulse. As the results obtained with this first procedure did not show a convincing phenotype of our male mutants, we then apply another protocol providing an extensive assessment of acoustic startle response from low (69 dB) to high (120 dB) intensities. Ten pulse intensities were used (over a background noise of 65dB): 69, 73, 77, 81, 85, 90, 95, 100, 110 and 120dB lasting for either 20 or 40 ms. Mice were acclimatised to the apparatus for two minutes before the first trial began. The first six trials consisted of six trials at 120 dBA, with three trials at each of the two possible stimulus durations. These trials served to stabilize the animals' startle response, and were not included in the overall analysis. Subsequently, the animals were presented with 5 blocks of discrete test trials. Each block consisted of twenty pulse-alone trials, one for each intensity and duration, presented in a pseudorandom order. The inter-trials interval was variable (9-19 s) with an average duration of 14 s. For all procedures, a total of 130 readings of the whole-body startle response were taken at 0.5-ms intervals (i.e., spanning across 65 ms), starting at the onset of the pulse stimulus. The average amplitude (in mV) over the 65 ms was used to determine the stimulus reactivity and further averaged across trials. A natural logarithmic transformation was applied in order to fulfill the normality criteria requested by parametric ANOVA.

Drug preparation All injectable solutions were freshly prepared on each experimental day. CHLOR (Sigma Aldrich, France) was dissolved in saline solution containing 1.25% DMSO (Sigma Aldrich, France) and 1.25% Tween80 (Sigma Aldrich, France). The same solution without drugs was used for the vehicle (VEH) control group. CHLOR was administered at the dose of 5mg/Kg in both acute and chronic studies, based on our previous dose-response studies in WT and Fmr1-KO mice (Lemaire-Mayo, Piquemal et al. 2020).

Brain and heart analyses After cardiac perfusion with 1x PBS followed by 4% paraformaldehyde, brains and hearts were removed. Brains were postfixed in 4% paraformaldehyde for 24 hours at 4ºC, in PBS for 24 hours at 4ºC, and then crioprotected in 30% sucrose for 24 hours at 4ºC. Serial coronal brain sections (150µm) were collected on a glass slide and directly mounted with Mowiol. Hearts were postfixed in 4% paraformaldehyde for 48 hours and then paraffin embedded. Serial coronal heart sections (8µm) were collected on a glass slide and stained with a regular hematoxylin-eosin protocol. For morphological analysis 1360x1024 images of the cortex, and CA1 hippocampus were obtained with an Olympus DP71 camera attached to an Olympus BX51 microscopy with an Olympus U-RFL-T source of fluorescence at -10x magnification. Measures from six sections per animal were averaged. Images of hematoxylin-eosin stained heart samples were obtained using visible light with an Olympus DP71 camera attached to an Olympus MVX10 MacroView Upright Microscope (zoom factor 1,25) Cardiomyocytes' areas were measured using ImageJ software.

Statistical analysis All data were analyzed with ANOVA using treatment and genotype as the between-subject factors and adding trials (for the rotarod), stimulus intensity (acoustic startle), 2min bins (social interaction) as the within-subject factors. Post-hoc comparisons were performed when a significant interaction genotype x treatment was found using Tukey's-Kramer test. Otherwise, separate one-way ANOVAs in each treatment group with genotype as the between subject factor were conducted, if appropriate. All analyses were carried out using Statview and PASW Statistics 18. All data are expressed as mean± SEM; p was set at 0.05.

RESULTS

Study 1: Behavioural effects of acute CHLOR treatment in CD mice

Mice received a single i.p. injection of VEH solution or CHLOR (5mg/Kg). One hour after injection, animals were submitted to the rotarod test, the open field, the social interaction test, and acoustic startle test with low intensity stimuli (72-90 dB). As expected, CD mice treated with VEH showed motor alterations, evident as an overall reduction in the latency to fall from the rotarod and hypoactivity in the open field (Fig. 1-A and-B), and deficits in social habituation (Fig. 1-C). The abnormalities in motor coordination in the rotarod test (Fig. 1-A) were attenuated by acute CHLOR administration that was able to significantly improve the motor learning abilities of mutant mice on the 3 rd trial [interaction genotype x treatment: F(1,41)=4.84, p<0. Mice received a daily i.p. injection of VEH solution or CHLOR (5mg/Kg) for 10 days before the beginning of behavioural testing. This experimental protocol was previously used in our study in Fmr1-KO mice where it showed marked behavioural effects of CHLOR [START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]. Behavioural tests were carried out 24hs after the last injection, in order to avoid acute confounding effects. They included rotarod test, assessment of overnight nest building, evaluation of self-grooming in a novel environment, direct social interaction and acoustic startle (69-120 dB) tests. Nest building behavior is an early and highly sensitive indicator of behavioural dysfunction [START_REF] Gaskill | Nest building as an indicator of health and welfare in laboratory mice[END_REF][START_REF] Jirkof | Burrowing and nest building behavior as indicators of well-being in mice[END_REF][START_REF] Kraeuter | The Nest Building Test in Mice for Assessment of General Well-Being[END_REF][START_REF] Neely | Nest Building Behavior as an Early Indicator of Behavioral Deficits in Mice[END_REF] , altered in several models of neuropsychiatric disorders [START_REF] Halene | Assessment of NMDA receptor NR1 subunit hypofunction in mice as a model for schizophrenia[END_REF][START_REF] Mo | Novel ethological endophenotypes in a transgenic mouse model of Huntington's disease[END_REF][START_REF] Carreno-Munoz | Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome[END_REF]. Self-grooming is also a naturally occurring behavior, that is more markedly expressed as an emotional response to a novel environment; it is therefore used as a sensitive indicator of enhanced anxiety, especially in genetic mouse models where other non-ethologically based tests fail to reveal emotional phenotypes [e.g., the Fmr1-KO mouse model for FXS, [START_REF] Gantois | Metformin ameliorates core deficits in a mouse model of fragile X syndrome[END_REF][START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]]. As expected, CD mice treated with VEH showed deficits in motor abilities and daily activities (Fig. 2-A andB), enhanced anxiety levels (Fig. 2-C), reduced social habituation (Fig. 2-D) and altered acoustic startle response (Fig. 2-E); all these abnormalities were attenuated or fully rescued by chronic CHLOR administration. The abnormalities of CD mice in motor coordination in the rotarod test (Fig. 2-A) were attenuated by chronic CHLOR administration, improving motor learning on the 3 rd trial [interaction genotype x treatment x trial: F(2,66)=2.95, p=0.06; genotype x treatment effect in separate ANOVA on trial 3: F(1,33)=9.42, p<0.01; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR]. CHLOR eliminated the reduced nesting abilities of CD mice [Fig. 2-B; interaction genotype x treatment effects: F(1,34)=4.16, p<0.05; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR], as well as their enhanced anxiety, i.e., self-grooming levels in a novel environment [Fig. 2-C; interaction genotype x treatment effects: F(1,33)=7.56, p<0.01; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR]. CHLOR also restored social habituation in the direct social interaction test (Fig. 2-D), as CD mice treated with CHLOR showed a time-dependent reduction in social investigation similar to WT mice, an habituation process that was absent in CD-VEH animals [genotype x treatment x 2-min bins: F(2,68)=5.41, p<0.01; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR on the last time bin]. Finally, CHLOR rescued the acoustic hypo-responsiveness of CD mice that was mostly evident at the highest stimulus intensities [Fig. 2-E; genotype x treatment x stimulus intensity: F(9,306)=5.75, p<0.0001; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR on the two highest intensities]. Fig. 2: Chronic behavioural effects of chlorzoxazone (CHLOR; 5mg/Kg) in male mice: Behavioural tests were conducted after 10 days of i.p. injections, with a 24hs interval from the last administration. They included the rotarod test for motor coordination (A), nest building assessment (B), anxiety levels measured by levels of self-grooming in a novel environment (C), social habituation during direct social interaction with a WT female (C), and acoustic startle response test (D, background level: 65dB). n=8-10; *=p<0.05; $= versus CD-CHLOR and WT-VEH. Data are expressed as Mean±SEM.

Study 3: Chronic effects of CHLOR on body, heart and brain abnormalities Mice received a daily i.p. injection of CHLOR during 10 days as in study 2 before being sacrificed for heart and brain morphological assessment. Before sacrifice, body weight was evaluated and mice underwent the marble-burying test, to confirm the behavioural chronic effects of CHLOR on this batch of mice. This test assesses a natural occurring defensive behaviour of laboratory mice, consisting in covering threatening objects, though it is sometimes employed as a test for anxiety or repetitive/obsessive behaviours. Therapeutic effects of CHLOR on the behaviour of CD mice were confirmed in this test, as CD-VEH animals displayed lower levels of marble burying, and these were normalized by CHLOR chronic treatment [interaction genotype x treatment: F(1,17)= 34.96, p<0.0001, Mean±SEM of number of buried marbles were: WT-VEH=17.2±0.74, CD-VEH=4.2±1.16, WT-CHLOR=15.17±0.75, CD-CHLOR=13.00±1.00]. As expected, body weight and brain weight of CD mice were significantly reduced when compared to their WT littermates, but these alterations were not alleviated by CHLOR chronic administration [Fig. 3-A andB; genotype effect, respectively: F(1,18)=46.44 and 102.6, p<0.0001; effects of treatment and of its interaction with genotype, all n.s.].

DISCUSSION

Our data demonstrate for the first time the efficacy of Chlorzoxazone (CHLOR) in rescuing the behavioural and cardiac abnormalities of CD mice, i.e., the last generation mouse model of WBS. These results suggest that potassium and especially BKCa channels may be altered in CD mice, either in terms of the expression of channel subunits, as observed in in vitro studies on neuronal samples derived from WBS patients [START_REF] Khattak | Human induced pluripotent stem cell derived neurons as a model for Williams-Beuren syndrome[END_REF], and/or in terms of channel functionality, as observed in other NDDs [START_REF] Laumonnier | Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation[END_REF][START_REF] Hebert | Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule[END_REF][START_REF] Zhang | Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice[END_REF]. Future studies are needed to specifically test this hypothesis, requiring electrophysiological and biochemical approaches to extensively assess potential alterations in the functional properties, as well as in the expression of BKCa channels in CD mice. These results will have to be then confirmed in WBS patients, in order to provide support to the hypothesis that channelopathies may be indeed a common etiopathological mechanism of multiple NDDs (Lee and Jan 2012). Our findings here provide convincing pre-clinical evidence for this hypothesis, as they fully match with the results we previously obtained in Fmr1-KO mice, showing the therapeutic effects of CHLOR (following the same experimental protocols used here) on behavioural FXS-like phenotypes (Lemaire-Mayo, Piquemal et al. 2020). We described therapeutic effects of CHLOR on both male and female CD mice, although the rescue of cardiac hypertrophy appeared less marked in female mutants (as shown in the supplementary material section). Although most pre-clinical studies on NDDs focus on male mice only, and no difference between male and female CD mice has emerged so far in their neuro-cardiobehavioural phenotypes [START_REF] Segura-Puimedon | Heterozygous deletion of the Williams-Beuren syndrome critical interval in mice recapitulates most features of the human disorder[END_REF]), a more extensive evaluation of the effects of CHLOR in female CD mice would be of high relevance to fully assess potential sex differences in the response to therapies. This issue is of special interest since WBS, in contrast to other NDDs, does not preferentially or more markedly affect the male human population [START_REF] Pankau | Statural growth in Williams-Beuren syndrome[END_REF][START_REF] Porter | Psychopathological and behavior impairments in Williams-Beuren syndrome: the influence of gender, chronological age, and cognition[END_REF], thus enhancing the importance of including female subjects in pre-clinical studies. The therapeutic impact of chlorzoxazone on the behavioural phenotype of CD mice was demonstrated here both following acute and chronic administration, thus showing efficacy also outside the acute time window. Our data therefore suggest that long-term plasticity mechanisms may be triggered by the chronic administration of CHLOR. Brain-derived neurotrophic factor (BDNF) is a good candidate for future studies in this direction, as its reduced expression has been described in the hippocampal areas of CD mice, an alteration that has been already rescued together with behavioural abnormalities by other non-pharmacological therapeutic interventions (Ortiz-Romero, [START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF]. It is also possible that chronic CHLOR may eliminate the behavioural and cardiac alterations of CD mice by rescuing the altered calcium homeostasis described at the neuronal and cardiomyocyte levels in these mutants (Ortiz-Romero, [START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF]. Indeed, alterations in calcium homeostatic processes have been identified in WBS patients, including hyper-calcaemia and -calciuria [START_REF] Sforzini | Renal tract ultrasonography and calcium homeostasis in Williams-Beuren syndrome[END_REF], and have been recently suggested as an important player in the development of WBS pathological phenotypes (Ortiz-Romero, [START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF].

While the identification of the specific mechanisms involved in the therapeutic effects of CHLOR requires further investigation, our data clearly demonstrate that the behavioural effects of this molecule are not mediated by a rescue of brain morphological alterations. CHLOR was indeed not able to attenuate the reduced brain weight or dendritic length found at both cortical and hippocampal levels in CD mice. As our treatment was limited to 10 days, starting at adult age, it is still possible that a rescue of these brain parameters (as well as of body weight loss) may require a longer period of administration and/or starting at earlier ages. Nonetheless, previous studies on therapeutic approaches in the CD model have also described behavioural and cardiac rescue with persisting alterations in brain weight and dendritic length/morphology (Ortiz-Romero, [START_REF] Ortiz-Romero | Epigallocatechin-3-gallate improves cardiac hypertrophy and short-term memory deficits in a Williams-Beuren syndrome mouse model[END_REF]. It is therefore possible that these brain morphological alterations may not play a crucial role in mediating the behavioural symptoms of WBS, or that their behavioural impact could be attenuated by activating alternative compensatory/plasticity brain mechanisms. The ability of CHLOR to rescue both the behavioural and the cardiac alterations of CD mice, suggests that this molecule can induce effects not only at the central brain level. This is not surprising, considering that BKCa channels are known to control not only neuronal, but also muscular excitability and smooth muscle tone [START_REF] Brenner | Vasoregulation by the beta1 subunit of the calcium-activated potassium channel[END_REF] . Nonetheless, this is the first evidence we obtained of non-behavioural effects of this molecule, as in our previous studies on Fmr1-KO mice we found therapeutic effects of CHLOR on the behavioural phenotypes, but not on other peripheral alterations, e.g., macro-orchidism [START_REF] Lemaire-Mayo | Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome[END_REF]. Further investigations are needed to evaluate potential disease-or organ-specific effects of CHLOR, especially relative to the central versus peripheral activation of BKCa channels. The therapeutic potential of CHLOR in treating both the cardiac and behavioural WBS-like symptoms is of crucial importance for the possible clinical applications of this drug. In fact, cardiovascular complications are the most common cause of health problems and even sudden death in WBS patients [START_REF] Wessel | Risk of sudden death in the Williams-Beuren syndrome[END_REF]). Moreover, the behavioral problems characterizing individuals with WBS can dramatically affect their quality of life, so that independent living is rarely achieved by these patients at adulthood [START_REF] Morris | Natural history of Williams syndrome: physical characteristics[END_REF]. Therefore, treatments that might alleviate the combination of these complex invalidating phenotypes deserve particular attention and converging research efforts.

  05 and treatment x trial F(2,84)=3.32, p<0.05; genotype x treatment effect in separate ANOVA on trial 3: F(1,43)=19.34, p<0.0001; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR]. Acute CHLOR fully eliminated the hypoactivity of CD mice in the open field [Fig.1-B; interaction genotype x treatment: F(1,45)=6.31, p<0.01; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR]. CHLOR also restored social habituation in the direct social interaction test (Fig.1-C), with CHLOR-treated CD mice showing a time-dependent reduction in social investigation similar to WT mice [genotype x treatment x 2-min bins: F(2,42)=3.33, p<0.05; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR on the last time bin]. CD mice treated with VEH showed a tendency to reduce sensory responsiveness in the acoustic startle test, especially at the highest intensities (Fig.1-D). Nonetheless, this phenotypic difference did not reach statistical significance [genotype x stimulus intensity: F(3,138)=2.29, p=0.08; treatment effect and its interactions: n.s.]; hence, we employed a more extensive evaluation of acoustic startle in our subsequent study with chronic administration.

Fig. 1 :

 1 Fig. 1: Acute behavioural effects of chlorzoxazone (CHLOR; 5mg/Kg): Behavioural tests were conducted 1h after a single i.p. injection and they included rotarod test for motor coordination (A), open field test for locomotor activity (B), social habituation during direct social interaction with a WT female (C), and acoustic startle response test (D) with low intensity stimuli (background level=66dB). n=6-14; *=p<0.05. Data are expressed as Mean±SEM.

Fig. 3 :

 3 Fig. 3: Chronic effects of chlorzoxazone (CHLOR; 5mg/Kg) on body and brain weight in male mice: Final measures of body weight (A) and brain weight (B) were taken after 10 days of i.p. injections, with a 24hs interval from the last administration. n=5-6; *=p<0.05. Data are expressed as Mean±SEM.When brain analyses were performed, CD animals showed an altered morphology in the motor cortex and hippocampus, and CHLOR treatment did not normalize these alterations, neither the reduced amount of YFP+ expressing neurons (Fig.4-Aand B, qualitative evaluation), nor the reduced dendritic length in both areas [Fig.4-C and D, genotype effect in cortex and hippocampus, respectively: F(1,10)= 25.76 and 83.38, p<0.001].

Fig. 4 :

 4 Fig.4: Chronic effects of chlorzoxazone (CHLOR; 5mg/Kg) on cortical and hippocampal morphology in male mice: Representative images of motor cortex (A; 4×) and hippocampus (B; 10×). Dendrite length of pyramidal neurons was measured in motor cortex (C) and in CA1 region (D). All measures were taken after 10 days of i.p. injections, with a 24hs interval from the last administration. n=3-4; *=p<0.05. Data are expressed as Mean±SEM. CD mice were characterized by cardiac hypertrophy (Fig.5), as demonstrated by the enhanced heart weight and the cardiomyocyte size compared to their WT littermates. These cardiac alterations were eliminated by chronic CHLOR administration, preventing both the enhanced heart weight [Fig.5-A; genotype x treatment interaction: F(1,18)=7.50, p<0.05; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR] and the enhanced cardiomyocytes' area [Fig. 5-B; genotype x treatment interaction: F(1,15)= 14.19, p<0.01; post-hoc: CD-VEH versus WT-VEH and versus CD-CHLOR].

Fig. 5 :

 5 Fig.5: Chronic effects of chlorzoxazone (CHLOR; 5mg/Kg) on cardiac hypertrophy in male mice: Cardiac hypertrophy was quantified through assessment of heart/body weight ratios (A) and cardiomyocyte size (B). Representative images of hematoxylin-eosin stained transverse sections of heart samples reveal the thickening of the left ventricular wall in CD-VEH mice (C). Mice were sacrificed after 10 days of i.p. daily injections, with a 24hs interval from the last administration. n=4-6; *=p<0.05. Data are expressed as Mean±SEM.

  FUNDING AND DISCLOSUREThis work has received funding from the Association "autour de Williams" to SP and VC, and by Ministerio de Ciencia e Innovación (SAF2016-78508-R; AEI/MINEICO/FEDER, UE) to VC ;MP, VLM, WC, and SP were funded also by CNRS and the University of Bordeaux. VLM, WC, EL, and SP are inventors on the patent: "Methods of treatment and/or prevention of disorders and symptoms related to BKCa and/or SK channelopathies" owned by Bordeaux University and assetsup.

ACKNOWLEDGEMENTS

The authors thank Delphine Gonzales and the genotyping facility of Neurocentre Magendie, funded by Inserm and LabEX BRAIN ANR-10-LABEX-43, for animal genotyping. We thank Elodie Poinama and Renata Hermez for their expert animal care, Thierry Lafont for technical assistance, Christophe Halgand and Loic Grattier for informatics support.


Olivier Godechot

Conclusion What finance manufactures

Why should we approach the study of finance in an alternative way when other disciplines -such as economics and financial theory -which are older, more legitimate and endowed with more substantial backing, have already been tackling this subject for over fifty years? Admirably, despite any misgivings, the rapid and varied development of a collection of studies on finance has nonetheless originated over the last fifteen years from a variety of disciplines (sociology, anthropology, political science, history, management sciences, geography). This has resulted from the dynamic academic practice of diversifying and reviving research subjects, though also because of a dissatisfaction with the inadequacy of standard approaches. But that is not all, as it has equally stemmed from a desire to understand a much deeper phenomenon: the sudden emergence of finance in social life.

 2012). Beyond the paradigmatic, theoretical or methodological diversity of this research, we can find a common approach: to study finance not only as a 1 . Originally, the expression Social Studies of Finance (Etudes Sociales de la Finance) was used in France to group together a collection of social science approaches dealing with financial markets, which offered alternatives to the dominant financial and economic theories. This entry via science and technology studies, inspired by research from Callon and Latour, was a strong initial component but not the only one. Later, certain authors had a tendency to identify the Social Studies of Finance in relation to this unique approach. 2 .

subject in itself, but also as a symptom of the contemporary financialisation of societies and their transformations. By studying the making of finance, we also study the magnitude of that which finance itself makes. Within these pages, we address the mechanisms and the social practices of contemporary capitalism that are often more visible in finance and are quite commonly disseminated across the rest of the economy from this financial hearth. After presenting research on contemporary financialisation, we demonstrate how the social studies of finance highlight three emblematic trends related to contemporary capitalism. These are, the -depoliticising -institutional policy of market order, a new knowledge regime combining academic knowledge with non-expert knowledge, and finally, the systematisation of 'greed'.

Approaching financialisation

Since the beginning of the 1980s, the financialisation of the world's economy has paradoxically manifested as a trivial phenomenon experienced by the whole world as part of everyday life, while at the same time being a difficult phenomenon to clearly define, measure or explain. First, both the outline and the definition of financialisation are difficult to establish precisely. Common proxies for this phenomenon include an increase in finance's share of the gross domestic product (GDP), profit or wages [START_REF] Godechot | Is finance responsible for the rise in wage inequality in France?[END_REF]2013;[START_REF] Krippner | The financialization of the American economy[END_REF][START_REF] Philippon | An international look at the growth of modern finance[END_REF][START_REF] Tomaskovic-Devey | Income dynamics, economic rents, and the financialization of the economy[END_REF]. One could be led to believe that a large portion of traditional finance (e.g. retail banking) is not relevant to this trend, as this concept brings to mind first and foremost the growing importance of financial markets in our modernday societies. A provisional Durkheimian definition of financialisation may be the growing amount of social energy devoted to the trading of financial instruments on financial markets. The volume of transactions taking place on the markets would therefore be a good candidate to measure it [START_REF] Godechot | Financialization is marketization! A study on the respective impact of various dimensions of financialization on the increase in global inequality[END_REF]. Nevertheless, restricting financialisation to the trade of financial instruments would lead us to miss an important aspect. The depth of the subprime crisis shows that part of the traditional banking system, which includes mortgages [START_REF] Fligstein | The Anatomy of the mortgage securitization crisis[END_REF], consumer credit or credit cards [START_REF] Poon | From new deal institutions to capital markets: Commercial consumer risk scores and the making of subprime mortgage finance[END_REF], has been deeply affected by new ideas stemming from financial markets, for example commodification, securitisation, liquidity, diversification, standardisation, fair value accounting, mathematical pricing models and delta-hedging techniques for arbitrage. Financialisation therefore cannot be limited to the growth of financial markets, but should instead be understood as the spread of the financial market's core logic beyond the bounds of its original sphere.

Second, the causes of financialisation are far from clear. Traditional explanations, in terms of demands for financial services or links between financial services and economic growth, struggle to account for long-term trends [START_REF] Philippon | An international look at the growth of modern finance[END_REF]. Deregulation policies have played a significant role in this movement (ibid.), specifically with respect to all the promarket policies detailed in the section that follows. In the same line, the combination of advances in financial theory and new technologies equally contributed to perform new markets (cf. third section). However, it would also appear that once the initial favourable conditions are aligned, market finance also increases in accordance with endogenous mechanisms (into which more research is still needed), creating as such a phenomenon of path dependency.

Third, the consequences of financialisation have not yet been fully measured. Traditionally, the main issue in economics is finance's contribution to economic growth, financial and economic stability and global crises (Aglietta and Rébérioux, 2004;[START_REF] Artus | La crise des subprimes[END_REF]. A growing section of the research also underlines finance's substantial impact on the increase of inequalities [START_REF] Atkinson | Top incomes in the long run of history[END_REF], due to the high-income salaries distributed at its core [START_REF] Bell | Bankers and their bonuses[END_REF][START_REF] Godechot | Is finance responsible for the rise in wage inequality in France?[END_REF]. It has also contributed substantially to spatial segregation and the increase in salary differences between global cities and hinterlands [START_REF] Godechot | Financiarisation et fractures socio-spatiales[END_REF], as well as to inequalities within nonfinancial firms [START_REF] Goldstein | Revenge of the managers: Labor cost-cutting and the paradoxical resurgence managerialism in the shareholder value era, 1984 to 2001[END_REF][START_REF] Lin | Financialization and US income inequality, 1970-2008[END_REF], notably due to the promotion of new forms of management and new ways of conceptualising companies, based exclusively on their financial value. Finally, financialisation emerges by activating powerful mechanisms (both within and outside of its own field) that will be further detailed in the following pages of this chapter.

A depoliticising policy: the institution of markets

Market exchange has not always been thought of as a fundamentally apolitical act. As such, during the emergence of the London Stock Market, at the beginning of the eighteenth century, transactions for certain securities took place preferentially between members of the same party, either the Whigs or the Tories [START_REF] Carruthers | City of capital. Politics and markets in the English financial revolution[END_REF]. In the context of consecutive political rivalry at the time of the Glorious Revolution, these two parties, whether by safeguarding it or conquering for it, indeed sought to maintain their control over the principal institutions lending money to the State and, in doing so, either establish or defend their own power over the State. The initial political dimension of financial exchange, especially visible in England during the eighteenth century, was nonetheless obscured by the effectively symbolic work of depoliticisation. De Goede (2005) provides a striking example of this process by revisiting the narrow and fragile threshold that financial markets established in the United States between gambling -unlawful and often forbidden -and financial speculation -which was considered lawful. Consequently, US stock market representatives succeeded in establishing, in the eyes of the authorities, a contrast between two very similar practices. The first being bets placed on prices that took place in certain cafés known as bucket shops, that were thought to exploit an irrational passion for gambling and destabilise the markets, and the second being futures trading on the stock markets by speculators, who were presumed to conduct sound calculations and therefore stabilise prices through their actions. De Goede thus proposes the groundwork for a Foucauldian history of financial markets which, through re-politicising institutions that present themselves in a naturalised and depoliticised manner, thus demonstrates the very contingent, political and in fine amendable nature of financial markets.

Financial markets are hence paradoxically political. They deny their political character by highlighting the primacy of financial interest and the non-partisan nature of their equilibria (above all guided by the principles of economics). However, in parallel, the principle financial maxim -that prices represent the value of securities -is no less than a political affirmation that implies furthermore a specific social order [START_REF] Ortiz | La 'valeur' dans l'industrie financière: le prix des actions cotées comme 'vérité' technique et politique[END_REF](Ortiz, , 2014a[START_REF] Ortiz | The limits of financial imagination: Free investors, efficient markets, and crisis[END_REF]. The paradoxically (a)political market order is not only the result of the endogenous dynamic of the financial sphere, it also owes its existence to policies related to the creation or the deepening of financial markets. [START_REF] Montagne | Les fonds de pension entre protection sociale et spéculation financière[END_REF] accordingly retraces the very specific legal conditions within the framework of which US pension funds, one of the pillars of contemporary financialisation, have been able to prosper. In actual fact, they depend upon a type of contract that is hardly representative of classical liberalism, known as a trust, which originates from the feudal world and that deems the beneficiary (the employee) a minor. The State's imperative to protect this individual as such leads less towards a freeing-up of the contract, than it does towards the surveying of trustees. In particular, the 1974 Employee Retirement Income Security Act (ERISA) urges pension funds to follow 'good financial practices' and forbids them to take into account any additional interests (such as retaining the recipients' employment) other than the financial interests of their employee recipients. This Act in fine moves less towards giving employees control over finance, than it does towards sealing off finance within itself.

Quite paradoxically, pro-market policy has not always been promoted solely by financial circles but also quite often by coalitions. Such coalitions were formed between social movements, finance groups and progressive governments -desiring to open up financing possibilities for those most in need or to improve market competition. [START_REF] Fligstein | The Anatomy of the mortgage securitization crisis[END_REF] consequently illustrate how the development of Mortgage Backed Securities was initiated by the Johnson administration in the context of its Great Society project. The US government had discovered that this type of security, backed by major governmental mortgage agencies (Fanny Mae and Freddie Mac), could be an innovative solution for promoting access to property for those on the inferior fringes of the middle class, without fuelling the then-threatening inflation. As [START_REF] Krippner | Capitalizing on crisis: The political origins of the rise of finance[END_REF] has shown, the dismantling of the Glass-Steagall Act -which since the 1930s separated investment banking from commercial banking -and more specifically, the dismantling of one of its emblematic measures, the Q Regulation -which limited interest rates on loans and deposits -were also brought on by social movements led by progressive actors such as Ralph Nader. Across the Atlantic in France, the major market transformation was carried out during the 1980s by the socialist government who, following the failure of stimulus policies, opted to promote market socialism [START_REF] Lagneau-Ymonet | Histoire de la Bourse[END_REF].

So, in spite of all this, are financial markets wholly embedded in institutions and institutional policies -including those that strive for dis-embeddedness [START_REF] Gayon | Maintenir l'ordre économique[END_REF])? Fligstein initiated this particular research programme by illustrating that traditional company governance, notably distinguished by its promotion of the multi-divisional firm and managers who originate from finance departments, owes a lot to legislation changes in the 1950s that limited vertical and horizontal integration in the name of competition [START_REF] Fligstein | The transformation of corporate control[END_REF]. Numerous studies have shown that the multidivisional firm model, whose privileged objectives were diversification and expansion, ceded its place to an organisational model focused on creating shareholder value [START_REF] Fligstein | The architecture of markets: An economic sociology of twenty-first-century capitalist societies[END_REF] and entirely centred on its core business activities, with the aim of maximising the company's stock market value. The firm was therefore split into as many profit centres as there were elementary units, with the value of each being measured in light of its potential resale on the market. A symptom of this transformation was the increasing power attributed to finance directors heading up companies and their appointment as chief financial officers (CFO), replacing chief operating officers (COO) [START_REF] Zorn | Here a chief, there a chief. The rise of the CFO in the American firm[END_REF][START_REF] Zorn | Managing investors: How financial markets reshaped the American firm[END_REF]. Clearly present at the outset of this movement is an institutional source, namely the transformation of the US tax system at the end of the 1970s [START_REF] Zorn | Here a chief, there a chief. The rise of the CFO in the American firm[END_REF]. The movement continued however thanks to the promotion of the shareholder value creation ideology, the 1980s hostile takeovers and the heightened role of financial analysts in determining prices [START_REF] Zorn | Managing investors: How financial markets reshaped the American firm[END_REF]. It also owed much to a logic endogenous to the economic field of the 1980s, which reunited and opposed three types of actors against one another. First off, the firm CEOs wanting to defend their power and their remuneration. Next, the corporate raiders who through leveraged buyout transactions -enabled thanks to the development of junk bonds -took control of major companies (or threatened to do so) in order to brutally restructure them. And finally, institutional investors, notably pension funds, preoccupied with avoiding certain transactions that could affect them negatively, such as greenmailing -when firms buyback shares from raiders for prices higher than those on the market [START_REF] Heilbron | The origins and early diffusion of 'shareholder value' in the United States[END_REF]. The diffusion of the shareholder value ideology, which favours less the shareholder than it does those said to represent them [START_REF] Jung | Agency theory as prophecy: How boards, analysts, and fund managers perform their roles[END_REF][START_REF] Goldstein | Revenge of the managers: Labor cost-cutting and the paradoxical resurgence managerialism in the shareholder value era, 1984 to 2001[END_REF], owes more to the 'field logic' than to a single actor, even if that actor happens to be the State itself [START_REF] Heilbron | The origins and early diffusion of 'shareholder value' in the United States[END_REF].

Approaching finance, its origins and its development, via its institutional embeddedness avoids turning financialisation into a self-emerging phenomenon that materialises out of thin air. Even though institutions do not provide an explanation for everything, they certainly play the role of founder and initiator. Moving beyond this initiator's role, policy from state institutions during the financial cycles of deregulation-crisis-reregulation [START_REF] Abolafia | Making markets. Opportunism and restraint on Wall Street[END_REF], notably that of the central bank [START_REF] Fligstein | The Anatomy of the mortgage securitization crisis[END_REF][START_REF] Krippner | Capitalizing on crisis: The political origins of the rise of finance[END_REF], has also been found to be stunningly short-sighted and incapable in the US of predicting the formation of a bubble or of softening the blow after it has burst. This is also the case with policy from governments, who only succeed in putting into place effective, less costly and restrictive rescue plans once the banking industry has managed to collectively coordinate itself under the leadership of its key players urged on by their declining health [START_REF] Woll | The power of inaction: Bank bailouts in comparison[END_REF].

A new regime of knowledge

The Social Studies of Finance not only examine how modern finance has taken root institutionally, they also consider the new regime of knowledge that finance encourages, which is characterised by a strong, but also transformative interaction between professional and academic knowledge. It is less a question of contesting such professional and academic knowledge, than it is of taking it up as subjects for study; and doing so consequently enables researchers to show how finance itself is structured and transformed by financial science.

The Social Studies of Finance (SSF) are therefore the principal grounds on which a research programme studying 'performativity'3 has been established, first launched by Michel Callon in 1998. According to Callon, the at times ritual criticism of neo-classical economics found in economic sociology articles is both unproductive and inaccurate. On the contrary, the utopian idea of homo oeconomicus has re-emerged as 'economics, in the broad sense of the term, performs, shapes and formats the economy, rather than observing how it functions' [START_REF] Callon | Introduction: The embeddedness of economic markets in economics[END_REF]. This revival of John Austin's concept has flourished in the field of SSF, to the point where several authors have considered it a key theme. The research produced as a result of this movement has shown that scientific statements are no longer just observations but, much like the celebrant's words 'I now declare you husband and wife', they also have the ability to transform the reality about which they speak.

In line with this perspective, [START_REF] Muniesa | Un robot walrasien. Cotation électronique et justesse de la découverte des prix[END_REF][START_REF] Muniesa | Market technologies and the pragmatics of prices[END_REF] established a genealogy related to a minor innovation, which occurred on the Paris Stock Market: the introduction of a fixing auction at market close. 4 This auction resulted from the crossing over of two quite distinct areas of activity. On one side, there were the market engineers, anxious about potential end-of-day manipulations with regard to establishing the closing price, a reference for many market agreements. On the other side, researchers from the academic world concerned with either financial theory or auction theory, who were comparing the quality of prices in various market structures. Organising a fixing auction for the market close, ten minutes after the end of continuous trading, appeared to be an elegant solution for establishing market equilibrium -à la Walras. It produced 'good quality' prices, founded on the accumulation of all sale and purchase offers made over a substantial period of time, and it was a very good response to the practical problem of price manipulation. It was enforced contrary to an alternative solution used on other stock markets, that of calculating an average of the prices 30 minutes before close, a solution considered by stock market experts to be more artificial and less revealing in terms of market forces. The field of economics therefore acted as a source of inspiration and, combined with market engineering, thus contributed towards performing the organisation of financial transactions. [START_REF] Mackenzie | An engine, not a camera. How financial models shape markets[END_REF], examining the fate of the Black Scholes formula in the financial industry, analysed another even more distinct case of the performativity of economics. In 1973 Black and Scholes published a theoretical solution to a then canonical academic issue in financial economics, that of the value of an option, a type of contract offering the right -but imposing no obligation -to buy a particular share on a given date. By modelling share prices as a Log-normal random walk, the two economists showed that the price of an option is a function of several elements, which included its duration, the interest rate, the price and the volatility of the share in question. When the two theorists began testing the formula on past data, they found it incorrectly described the relations between prices. However, a short time after the formula was published, prices began to behave just like it had indicated.

The various stages of this example of 'performativity' have been explained in detail by MacKenzie. In the mid-1970s, the price listings were sold off by one of the formula's creators. These listings described the theoretical value of options in relation to the evolution of current market prices. They were subsequently used by traders on the market to locate expensive and cheap options, allowing them to engage in arbitrage by selling off the former and buying up the latter. This 'performing' of the market in line with the formula, insists MacKenzie, does not correspond to a situation whereby the market adopts the 'only genuine solution' to the problem of pricing. The formula relied on noteworthy approximations and simplifications, in particular the hypothesis of the Log-normality of prices, that is to say the very weak probability of extreme variations. The crash of 1987 during which the market fell by more than 20 per cent in a single day would have been improbable sales price, a transaction is concluded.

according to the modelling used above. Financial theory, which deals with the pricing of complex financial products and portfolio allocation, therefore overturns the rationale of scientific discovery. In essence, it transforms financial reality to a much greater extent than it uncovers the relations that structure it. Such 'performing' is not limited to canonical theories of financial science. Certain seemingly insignificant technical mechanisms of representation can play a determining role in the action. [START_REF] Zuckerman | The categorical imperative: Securities analysts and the illegitimacy discount[END_REF]2004) as such underlines the impact of categories employed by actors. In his work, financial analysts are seen to perceive firm value through economic sectors. Categories are therefore all the more meaningful to analysts in that they constitute a framework for their professional specialisation. Multi-sector firms, incoherent from the perspective of categorical division, are therefore often monitored by analysts coming from vastly different specialisations. This incoherent network position generates fewer, less favourable and more contradictory valuations; consequently prompting the undervaluation of a company's securities on the stock market, in addition to triggering stronger volatility and higher transaction volumes when results are announced.

It is impossible though to reduce the scientific research programme analysing the regime of financial knowledge to the study of the performativity of academic financial theory. For one reason, it is not always performed with success [START_REF] Jung | Agency theory as prophecy: How boards, analysts, and fund managers perform their roles[END_REF]. In certain cases, even counter-performativity could be mentioned [START_REF] Mackenzie | An engine, not a camera. How financial models shape markets[END_REF], particularly that of the anomalies revealed by behavioural finance. Even just the naming of anomalies (such as the 1st of January effect, which is the likelihood of a price rise occurring on this date) can lead to their disappearance (simply through the exploitation of opportunities for arbitrage). For another reason, the programme of performativity often forgets to include cultural, social and institutional reasons that can lead to different theories being adopted. The programme of performativity can therefore be expanded via a study of financial reasoning in all its diversity [START_REF] Tadjeddine | Les prises cognitives de la rationalité. Une typologie des décisions spéculatives[END_REF]. [START_REF] Smith | Success and survival on Wall Street. Understanding the mind of the market[END_REF] is without doubt one of the first sociologists to propose a detailed analysis of financial beliefs and behaviours through the development of a gallery of flamboyant profiles that feature financial participants. He distinguishes six diverse categories of true believers who think the market is systematically governed by forces. First up are the 'Fundamentalists', who believe that economic forecasts, in particular those related to dividends, are what determine prices. Next, there are those partial to the theory of 'Insiders' who believe prices are determined by major players who have access to privileged information, which leads them to lie in wait for any related rumours. The Cyclist-Chartists make their predictions on the basis of 'resistance lines', straight lines they trace between the extrema (maxima and minima) of prices. Then there are the proponents of the Trader style, who follow their feelings trying to sense the market's movements, while Efficient Market Believers consider that the only thing that matters is accurately replicating the global market in their portfolios. Finally, the 'Transformational Idea Adherents' seek out economic ideas likely to radically change the world, like for example the 'new economy'.

Less specific with regard to the spread of possible beliefs and their ways of functioning, within my own research [START_REF] Godechot | Les traders. Essai de sociologie des marchés financiers[END_REF](Godechot, , 2016a) I have examined a variety of financial practices identified in trading rooms involved in the commercialisation and arbitrage of sophisticated derivatives, and have established connections between these and individual career paths in finance, the capital owned by actors and, lastly, the structure of the positions they occupy in the room. Social and educational background, in addition to the means of initiation into financial activities, which often occurs via a mentor, produce ways of seeing the market that are not only persistent, but that also represent a system of likes and dislikes -that never runs dry of tireless controversies -similar in a way to the debates commonly found amongst IT users: Mac or PC, Windows or Linux, etc. As it were, three financial strategies that are easily identified via a questionnaire -mathematical arbitrage, chartist analysis and economic analysis -stand opposed to one another in that they create opposition between individuals who either come from different educational backgrounds or who hold different positions in the trading room or who maintain different market perspectives. Followers of mathematical arbitrage here find an alternative way of continuing the preparatory school where they developed an enchanted relationship with academic knowledge. Like the followers of economic analysis, they often find chartists to be inept, and the two compete to provide explanations for its wholly unfounded use. They are however also quite often opposed to macro-economic analysis as, according to them, it lacks precision. Followers of this latter analysis in contrast highlight the limited character of arbitrage; i.e. the small wins, which deep down are not based on a global understanding of the market, but only on the very narrow relations between various securities from the same family. Finally, the followers of chartist analysis, often hailing from working class backgrounds, hold in high regard the counter-cultural side of this pagan-like knowledge. Although its methods generally lead to ambiguous recommendations, they believe charts enable them to outdo even those financial actors using the most legitimate forms of knowledge (Godechot, 2008a). This description of these three opposing camps jostling around within one space -connected by a continuum of hybrid positions much like a 'bazaar of rationality', where everyone brings what they have to offer and positions themselves in relation to what others are offering, seeking to both associate and differentiate themselves from one another -allows us to think differently about rationality; and not just as an a priori given for social actors, like economists' models make it out to be, but as a structural process for acquiring and constructing reasoning (Godechot, 2016a). The guiding principle of this bazaar of rationality is therefore, either consciously or unconsciously, 'economic', as it incites individuals to take up those techniques for which they feel the most affinity, for which they possess the most capital and the necessary predisposition. Concerning the nature of the market, this debate between supporters of different methods in one way shows that the market is a reflexive institution. The market is neither fundamentalist, nor chartist, nor does it conform to mathematic efficiency. It is instead the product of this clash between differing points of view (Godechot, 2008a).

If knowledge is at this point constitutive of contemporary finance, we can therefore deduce that the financial crisis itself is also a matter of knowledge. As has been convincingly demonstrated by Donald MacKenzie (2011) in relation to the subprime crisis. The most toxic financial products, the MBS-CDOs -debt obligations backed by mortgage portfolios -were potentially born from two types of knowledge, one relative to mortgage securitisation (for the first stage of securitisation) and the other relative to corporate bonds securitisation (for the second stage of securitisation). Banks and ratings agencies, however, entrusted the valuation of mortgage products to services involved in the securitisation of corporate bonds, who in doing so transposed logical reasoning specific to the valuation of corporate bonds portfolios across to MBS-CDOs. However, in contrast with corporate portfolios, there are no price series for mortgage portfolios enabling the autocorrelation of defaults and anticipated repayments to be calculated. To make up for this lack of information, the banks and ratings agencies adopted an arbitrary level of correlation (a 'Gaussian Copula') of 0.3, which corresponded to the mean autocorrelation for defaults by firms within the same sector. The avalanche of defaults following the 2007 interest rate rise shows that this conceptual decision, the product of a conceptual and social division of labour in asset valuation activities, seriously underestimated the autocorrelation of defaults, leading as a result to the most serious financial crisis since the Great Depression.

The systematisation of 'greed'

The unilaterality of the challenges uniquely faced in finance -namely, providing profit for corporations and bonuses for employees -in addition to the degree of technicality involved in economic calculations and transaction arrangements, and the lively competition that rules over markets, all contribute towards developing the autonomous separation of this field from others, in addition to establishing highly rationalised practices. Numerous authors (Abolafia, 1996: 14-37;[START_REF] Godechot | Les traders. Essai de sociologie des marchés financiers[END_REF]Zaloom, 2006: 111-125) have examined this Weberian process of behaviour rationalisation and questioned whether the financial world was not in some way contributing to bringing the fictional being of homo oeconomicus [START_REF] Callon | Introduction: The embeddedness of economic markets in economics[END_REF] into actual existence, thanks to work spaces equipped with computing systems, the continuous accounting of business activity and, most importantly, due to strong monetary incentives. Studying incentives is a good way of understanding rationalisation, because their impact is without doubt more striking in this sphere than elsewhere. However, carrying out such a study means avoiding two pitfalls. The first involves considering rationalisation to be so powerful that it will ultimately culminate in the arrival, at the heart of the financial markets, of a perfect and accomplished homo oeconomicus, wholly validating the scientific approaches (mainstream economics) founded exclusively on this hypothesis, even if done so for 'ill-founded reasons', eventually rendering any development of alternative approaches redundant. The second pitfall consists of believing that all incentives have been rationally calibrated in order to produce behaviours aligned in favour with the shareholder's interests.

Emphasising more or less this dimension, ethnographic studies show that compensations, in particular bonuses, constitute the gravitational centre of financial activity [START_REF] Abolafia | Making markets. Opportunism and restraint on Wall Street[END_REF][START_REF] Godechot | Les traders. Essai de sociologie des marchés financiers[END_REF][START_REF] Godechot | Wages, bonuses and appropriation of profit in the financial industry[END_REF]Ortiz, 2014a;[START_REF] Roth | Selling women short: Gender and money on Wall Street[END_REF][START_REF] Zaloom | Out of the pits: Traders and technology from Chicago to London[END_REF]. High remuneration indeed greatly steers behaviours, though without achieving the equilibrium described by neoclassical economics. Indeed, on the whole the extremely elevated compensation levels present in finance illustrate that neither the financial securities market, nor the financial labour market are efficient. If salaries were to follow the predictions provided by principal-agent models, then they would consist of a much lower fixed salary, even a negative salary (< 0), so that the utility in these financial roles would be equivalent to that encountered in non-financial professions that require the same skills [START_REF] Godechot | Le capital humain et les incitations sont-ils les deux mamelles des salaires dans la finance[END_REF][START_REF] Godechot | Wages, bonuses and appropriation of profit in the financial industry[END_REF]. The fact that certain employees are able to acquire the power to hold-up a corporation constitutes a better explanation for the level of wages than the idea of optimal incentives to work hard [START_REF] Godechot | Wages, bonuses and appropriation of profit in the financial industry[END_REF]. Studying an exemplary case concerning holdups allows us to stylise how salaries are actually determined. In 2000, two trading room managers working for a major bank obtained €10 and €7 million in bonuses by brandishing the credible threat to leave and take the teams they managed with them to a rival bank. This case illustrates the logic of the holdup, namely that having control of transferable assets provides the means to threaten the company with damages if they refuse a renegotiation that favours the employee. This technique is even more frequent considering that protection against it is relatively inefficient. It leads us to observe the financial industry's labour market in a different way; as though it was less like a market representing people and individual skills, and more like a market of corporate assets collectively produced and carried off by people who organise their transfer [START_REF] Godechot | Getting a job in finance. The role of collaboration ties[END_REF].

Studying compensation is also important for understanding financial behaviours. Following the crisis, the wider public and most economists emphasised the fact that remunerations could encourage risk-taking and help to explain the crisis [START_REF] Cheng | Yesterday's heroes: Compensation and risk at financial firms[END_REF]. To this well-known element, perhaps overestimated in the public debate, we can add another that remains underrated [START_REF] Godechot | Les bonus accroissent-ils les risques?[END_REF]. Bonuses not only lead to excess risk-taking (with only the positive amount of the profit being rewarded, while negative amounts carry no penalties), they also lead to the deformation of risk measurement or more precisely the politicisation of risk measurement in financial corporations. Indeed, as long as the equivalent of 100-200 per cent of the bulk of fixed salaries is distributed each year in the form of bonuses and as long as these bonuses depend on accounting measures based on the revenues net of the costs of risk, then the temptation to underestimate the risks incurred so as to maximise bonuses will remain great, and even more so when they involve new financial products that are difficult to value. Moreover, in major banks, risk management departments do not fully assume their supervisory role. To begin with, faced with this role, front office staffs enjoy great legitimacy and a powerful ability to impose certain risk measurements on other parties, to inherently favour their own position. Second, bonuses for risk management departments often depend at least indirectly on the percentage of the bonus pool duly granted to the front office. Finally, those in risk management often have their sights set on trading professions. They must therefore monitor people for whom they would very much like to work for in the future. This therefore means not being too overzealous, so as to avoid upsetting them. This greed-based logic also fuels the two additional logics discussed above: the depoliticising institution of markets and the transformational overlapping of academic and professional knowledges. The article by [START_REF] Jung | Agency theory as prophecy: How boards, analysts, and fund managers perform their roles[END_REF] articulates how the partial performing of the neoclassical academic theory of firms, which promotes a depoliticised firm uniquely at the service of its shareholders, owes much to the remuneration conditions of portfolio managers handling pension funds. Paid in the form of bonuses, they promote the elements of this theory in line with this form of extremely short-term compensation, and abandon all others.

Conclusion: the advance of finance

This overview of social studies research centred on finance, which is undoubtedly incomplete, aims to illustrate the advance of finance, in the dual sense of the term. On one hand, illustrating the progress finance has made and, on the other, the lead it has taken ahead of other economic sectors and more generally the rest of society. A comprehensive evaluation of the social effects of this advance has, as yet, only just begun. While mainstream economics generally tends to underline any shared benefits, other social sciences, which are more critical, often focus exclusively on the costs. Although finance subjects (certain) people to new constraints, it also liberates (others) from traditional dependencies [START_REF] Fontaine | The moral economy. Poverty, credit, and trust in early modern Europe[END_REF]). As a final example of this, the development of credit scoring in the US clearly demonstrates how transforming the way credit equivalences are established can alter the types of actors who are either favoured or disfavoured. The credit score system indeed replaces a method of credit distribution founded on affiliations with specific categories (i.e. gender, race, age) and local social reputations, with one instead founded on one's personal debt and repayment history [START_REF] Fourcade | Classification situations: Life-chances in the neoliberal era[END_REF][START_REF] Poon | From new deal institutions to capital markets: Commercial consumer risk scores and the making of subprime mortgage finance[END_REF]. Furthermore, the academic debate a propos the costs and benefits of the advance of finance is but a subset of the political and social debate surrounding this same issue. Policy choices reflect a reorientation in relation to this subject. After three decades of policies stimulating the advance of finance, now, following the 2008 financial crisis, societies instead seek to contain it without, for the moment, having found the necessary solutions.

. Developed in a collection of works published in 1962 by the philosopher Austin (How to do things with words), the concept of 'performativity' describes the characteristic of language that is its influence over the reality it describes.

. Fixing here refers to a discrete call auction wherein the auctioneer has taken time to gather together all the sales and purchasing orders before establishing the price. It sits in opposition to continuous trading, where as soon as an offering price equals the