Biology subjects

Le Magueresse, C.

Publications and source records attributed to Le Magueresse, C..

5 recordsLinked to original sources

bioRxiv2025

WNK-Dependent Phosphorylation of Gephyrin Tunes GABAA Receptors at Inhibitory Synapses and Modulates Anxiety Behavior

The role of the chloride-sensitive kinase WNK1 and its effector SPAK in the brain remains poorly understood. Here, we identify a regulatory mechanism involving WNK signaling that directly controls the synaptic diffusion and clustering, as well as the membrane stability and endocytosis of inhibitory GABAA receptors (GABAARs). We show that activation of WNK signaling stabilizes GABAARs at inhibitory synapses, while inhibition enhances receptor internalization. This regulation depends on the phosphorylation state of two previously uncharacterized residues in the central linker region of the gephyrin scaffold protein. Modulating WNK activity alters neuronal activity and the kinetics of GABAergic currents. In vivo, expression of a phospho-mimetic form of gephyrin at WNK-targeted sites produces anxiolytic effects. By orchestrating the recruitment of GABAARs at inhibitory synapses, the WNK pathway emerges as a master regulator of GABAergic transmission and establishes chloride as a bona fide second messenger in inhibitory synaptic signaling. SignificanceSynaptic transmission relies on signaling pathways that control how neurotransmitter receptors move and stabilize at synapses. Many of these pathways use calcium as a second messenger. In contrast, how chloride might regulate synapses has remained unclear. In this study, we identify a chloride-sensitive pathway involving the WNK1 kinase and its partner SPAK, which controls the movement and stability of inhibitory GABAA receptors at synapses. This occurs through the phosphorylation of gephyrin, a key scaffolding protein, at two newly identified sites. Our results show that intracellular chloride can act as a second messenger, reshaping inhibitory synapses and altering behavior in mice, including reducing anxiety-like responses.

neuroscience↗

bioRxiv2022

5-HT1A and 5-HT2B receptor interaction and co-clustering regulates serotonergic neuron excitability

Many psychiatric diseases including depression, schizophrenia and anxiety have been associated with serotonin (5-HT) neuron dysfunction. Pacemaker-like firing of raphe 5-HT neurons was proposed to be under unique 5-HT1A receptor-mediated autoinhibition. We previously showed that 5-HT2B receptors were expressed by 5-HT neurons together with 5-HT1A receptors. However, functional consequences on 5-HT neurons of putative interaction between these receptors are unknown. Using co-immunoprecipitation, BRET, confocal and super-resolution microscopy in hippocampal and 5-HT neurons, we present converging evidence that 5-HT1A and 5-HT2B receptors can form heterodimers and co-cluster at the surface of dendrites. 5-HT2B receptor clusters were redistributed upon 5-HT1A receptor expression supporting functional interactions between the two receptors. Furthermore, 5-HT2B receptor expression prevented agonist-induced internalization of 5-HT1A receptors, whereas 5-HT1A receptors mimicked the clustering effect of 5-HT2B receptor stimulation on its surface expression. The functional impact of this interaction in-vivo was assessed by recording 5-HT neuron excitability from mice lacking 5-HT2B receptors in 5-HT neurons. Upon 5-HT1A receptor stimulation, the firing activity of 5-HT neurons was increased in the absence of 5-HT2B receptors and decreased in their presence through regulation of SK channels, thus demonstrating functional output of this interaction in controlling 5-HT neuron firing activity.

neuroscience↗

bioRxiv2022

Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills

The proper maturation of emotional and sensory circuits requires a fine tuning of serotonin (5-HT) level during early postnatal development. Consistently, dysfunctions of the serotonergic system have been associated with neurodevelopmental psychiatric diseases, including autism spectrum disorders (ASD). However, the mechanisms underlying the developmental effects of 5-HT remain partially unknown, one obstacle being the action of 5-HT on different cell types. Here, we focused on microglia, which play a role in brain wiring refinement, and we investigated whether the control of these cells by 5-HT is relevant for neurodevelopment and spontaneous behaviors. Since the main 5-HT sensor in microglia is the 5-HT2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditionally invalidating Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia neonatally impacts the phagolysosomal compartment of these cells and their proximity to synapses, and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT2B receptors leads to adult hyperactivity in a novel environment and behavioral defects in sociability and flexibility. Importantly, we show that these behavioral alterations result from a developmental effect, since they are not observed when microglial Htr2b invalidation is induced later, at P30 onward. Thus, a primary alteration of 5-HT sensing in microglia, during a critical time window between birth and P30, is sufficient to impair social and flexibility skills. This link between 5-HT and microglia may explain the association between serotonergic dysfunctions and behavioral traits, like impaired sociability and inadaptability to novelty, which are prominent in several psychiatric disorders such as ASD.

neuroscience↗

bioRxiv2020

Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex (PFC). We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia, and shed light on the underlying cellular mechanisms.

neuroscience↗

bioRxiv2018

Early life stress impairs postnatal oligodendrogenesis and adult behavior through activity-dependent mechanisms

Exposure to stress during early life (infancy/childhood) has long-term effects on the structure and function of the prefrontal cortex (PFC) and increases the risk for adult depression and anxiety disorders. However, little is known about the molecular and cellular mechanisms of these effects. Here we focused on changes induced by chronic maternal separation during the first two weeks of postnatal life. Unbiased mRNA expression profiling in the medial PFC (mPFC) of maternally separated (MS) pups identified an increased expression of myelin-related genes and a decreased expression of immediate early genes. Oligodendrocyte lineage markers and birthdating experiments indicated a precocious oligodendrocyte differentiation in the mPFC at P15, leading to a depletion of the oligodendrocyte progenitor pool in MS adults. We tested the role of neuronal activity in oligodendrogenesis, using designed receptors exclusively activated by designed drugs (DREADDs) techniques. hM4Di or hM3Dq constructs were transfected into mPFC neurons using fast-acting AAV8 viruses. Reduction of mPFC neuron excitability during the first two postnatal weeks caused a premature differentiation of oligodendrocytes similar to the MS pups, while chemogenetic activation normalized it in the MS animals. Bidirectional manipulation of neuron excitability in the mPFC during the P2-P14 period had long lasting effects on adult emotional behaviours and on temporal object recognition: hM4Di mimicked MS effects, while hM3Dq prevented the pro-depressive effects and short term memory impairment of MS. Thus, our results identify neuronal activity as a critical target of early life stress and demonstrate its function in controlling both postnatal oligodendrogenesis and adult mPFC-related behaviors.

animal behavior and cognition↗