Control of a hippocampal recurrent excitatory circuit by cannabinoid receptor-interacting protein Gap43

The type-1 cannabinoid receptor (CB1R) is widely expressed in excitatory and inhibitory nerve terminals, and by suppressing neurotransmitter release, its activation modulates neural circuits and brain function. While the interaction of CB1R with various intracellular proteins is thought to alter receptor signaling, the identity and role of these proteins are poorly understood.Using a highthroughput proteomic analysis complemented with an array of in vitro and in vivo approaches in the mouse brain, we report that the C-terminal, intracellular domain of CB1R interacts specifically with growth-associated protein of 43 kDa (GAP43). The CB1R-GAP43 interaction occurs selectively at mossy cell axon boutons, which establish excitatory synapses with dentate granule cells in the hippocampus. This interaction impairs CB1R-mediated suppression of mossy cell to granule cell transmission, thereby inhibiting cannabinoidmediated anti-convulsant activity inmice. Thus, GAP43 acts as a synapse typespecific regulatory partner of CB1R that hampers CB1R-mediated effects on hippocampal circuit function

Role of serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex : involvement in synaptic transmission, plasticity and cognition

La sérotonine est impliquée dans de nombreuses fonctions physiologiques comme la régulation de l’appétit, du sommeil, de la douleur, de l’humeur et de la cognition. Elle agit par l’intermédiaire de différents récepteurs dont la plupart sont couplés aux protéines G. Parmi ceux-ci, les récepteurs 5-HT2A et 5-HT6 suscitent un intérêt particulier car ils sont la cible de nombreux agents thérapeutiques, comme les antidépresseurs et les antipsychotiques de dernière génération. Ces molécules administrées pour traiter la schizophrénie ont des effets bénéfiques sur les symptômes positifs (hallucinations, délires) et négatifs (manque de motivation). Cependant, ils n’ont que peu d’effets sur les déficits cognitifs (troubles de la mémoire de travail, de l’attention, asociabilité) qui compromettent l'intégration sociale et professionnelle des patients ainsi que leur qualité de vie. Ces déficits sont en grande partie retrouvés chez les consommateurs chroniques de cannabis durant l’adolescence suggérant des mécanismes pathologiques communs. La découverte de nouvelles stratégies thérapeutiques pour traiter ces déficits cognitifs constitue donc un enjeu de santé publique majeur.Au cours de mon travail de thèse, j’ai étudié le rôle des récepteurs de la sérotonine, en me focalisant sur les récepteurs 5-HT2A et 5-HT6, dans la modulation de la transmission et la plasticité synaptique au niveau du cortex préfrontal. En combinant des approches biochimiques à des analyses électrophysiologiques et comportementales, j’ai dans un premier temps démontré l'implication des récepteurs 5-HT2A exprimés au niveau des synapses thalamocorticales dans l’induction de la plasticité synaptique et dans la mémoire associative. Dans un deuxième temps, j’ai déterminé les bénéfices du blocage précoce des récepteurs 5-HT6 sur les déficits cognitifs induits dans un modèle neurodéveloppemental de schizophrénie et un modèle de consommation chronique de cannabis durant l’adolescence. Cette étude permet ainsi d’envisager de nouvelles stratégies thérapeutiques pour prévenir l’apparition des déficits cognitifs observés dans les maladies psychiatriques, notamment chez les sujets à risque.Serotonin is involved in many physiological functions, such as the control of appetite, sleep, pain, mood and cognition. This major neuromodulator acts via different receptors, which are, for the most part, coupled to G-proteins. Among these, 5-HT2A and 5-HT6 receptors are of particular interest since they are the target of many therapeutic drugs, such as antidepressants and last-generation antipsychotics. These are administered to treat schizophrenia and have beneficial effects on positive (hallucinations, delusions) and negative (lack of motivation) symptoms. Nevertheless, they poorly control cognitive deficits (impaired working memory, decreased attention, alteration in social cognition) which severely compromise the social integration of patients and their quality of life. These deficits are also found in chronic cannabis users during adolescence, suggesting common pathological mechanisms. Therefore, the discovery of new therapeutic strategies to treat these cognitive deficits is a major public health issue.During my thesis work, I studied the role of serotonin receptors, focusing on 5-HT2A and 5-HT6 receptors, in the modulation of synaptic transmission and plasticity in the prefrontal cortex. By combining biochemical approaches with electrophysiological and behavioral analyses, I initially demonstrated that 5-HT2A receptors expressed at thalamocortical synapses play a crucial role in the induction of synaptic plasticity and in associative memory. Secondly, I demonstrated the benefits of early blockade of 5-HT6 receptors for preventing cognitive deficits induced in a neurodevelopmental model of schizophrenia and a model of chronic cannabis abuse during adolescence. These studies offer new therapeutic strategies to prevent the emergence of cognitive deficits and conversion to schizophrenia in at-risk subjects

Growing Evidence for Heterogeneous Synaptic Localization of 5-HT2A Receptors

International audienceThe serotonin 2A (5-HT2A) receptor subtype continues to attract attention as a target for numerous psychoactive drugs including psychedelic hallucinogens, antidepressants, anxiolytics, and atypical antipsychotics. 5-HT2A receptors are a principal G protein-coupled receptor subtype mediating the excitatory effects of serotonin. Nonetheless, pre- vs postsynaptic localization of 5HT2A receptors, relative to glutamatergic synapses, has remained controversial. Here, we discuss recent findings highlighting the existence and roles of presynaptic 5-HT2A receptors in regulating glutamatergic transmission and cognition

Growing Evidence for Heterogeneous Synaptic Localization of 5-HT2A Receptors

International audienceThe serotonin 2A (5-HT2A) receptor subtype continues to attract attention as a target for numerous psychoactive drugs including psychedelic hallucinogens, antidepressants, anxiolytics, and atypical antipsychotics. 5-HT2A receptors are a principal G protein-coupled receptor subtype mediating the excitatory effects of serotonin. Nonetheless, pre- vs postsynaptic localization of 5HT2A receptors, relative to glutamatergic synapses, has remained controversial. Here, we discuss recent findings highlighting the existence and roles of presynaptic 5-HT2A receptors in regulating glutamatergic transmission and cognition

Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses

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Presynaptic serotonin 2A receptors modulate thalamocortical plasticity and associative learning

International audienceHigher-level cognitive processes strongly depend on a complex interplay between mediodorsal thalamus nuclei and the prefrontal cortex (PFC). Alteration of thalamofrontal connectivity has been involved in cognitive deficits of schizophrenia. Prefrontal serotonin (5-HT)2A receptors play an essential role in cortical network activity, but the mechanism underlying their modulation of glutamatergic transmission and plasticity at thalamocortical synapses remains largely unexplored. Here, we show that 5-HT2A receptor activation enhances NMDA transmission and gates the induction of temporal-dependent plasticity mediated by NMDA receptors at thalamocortical synapses in acute PFC slices. Expressing 5-HT2A receptors in the mediodorsal thalamus (presynaptic site) of 5-HT2A receptor-deficient mice, but not in the PFC (postsynaptic site), using a viral gene-delivery approach, rescued the otherwise absent potentiation of NMDA transmission, induction of temporal plasticity, and deficit in associative memory. These results provide, to our knowledge, the first physiological evidence of a role of presynaptic 5-HT2A receptors located at thalamocortical synapses in the control of thalamofrontal connectivity and the associated cognitive functions

Retrograde adenosine/A2A receptor signaling facilitates excitatory synaptic transmission and seizures

Summary: Retrograde signaling at the synapse is a fundamental way by which neurons communicate and neuronal circuit function is fine-tuned upon activity. While long-term changes in neurotransmitter release commonly rely on retrograde signaling, the mechanisms remain poorly understood. Here, we identified adenosine/A2A receptor (A2AR) as a retrograde signaling pathway underlying presynaptic long-term potentiation (LTP) at a hippocampal excitatory circuit critically involved in memory and epilepsy. Transient burst activity of a single dentate granule cell induced LTP of mossy cell synaptic inputs, a BDNF/TrkB-dependent form of plasticity that facilitates seizures. Postsynaptic TrkB activation released adenosine from granule cells, uncovering a non-conventional BDNF/TrkB signaling mechanism. Moreover, presynaptic A2ARs were necessary and sufficient for LTP. Lastly, seizure induction released adenosine in a TrkB-dependent manner, while removing A2ARs or TrkB from the dentate gyrus had anti-convulsant effects. By mediating presynaptic LTP, adenosine/A2AR retrograde signaling may modulate dentate gyrus-dependent learning and promote epileptic activity

Chemogenetic regulation of the TARP-lipid interaction mimics LTP and reversibly modifies behavior

Summary: Long-term potentiation (LTP), a well-characterized form of synaptic plasticity, is believed to underlie memory formation. Hebbian, postsynaptically expressed LTP requires TARPγ-8 phosphorylation for synaptic insertion of AMPA receptors (AMPARs). However, it is unknown whether TARP-mediated AMPAR insertion alone is sufficient to modify behavior. Here, we report the development of a chemogenetic tool, ExSYTE (Excitatory SYnaptic Transmission modulator by Engineered TARPγ-8), to mimic the cytoplasmic interaction of TARP with the plasma membrane in a doxycycline-dependent manner. We use this tool to examine the specific role of synaptic AMPAR potentiation in amygdala neurons that are activated by fear conditioning. Selective expression of active ExSYTE in these neurons potentiates AMPAR-mediated synaptic transmission in a doxycycline-dependent manner, occludes synaptically induced LTP, and mimics freezing triggered by cued fear conditioning. Thus, chemogenetic controlling of the TARP-membrane interaction is sufficient for LTP-like synaptic AMPAR insertion, which mimics fear conditioning

Excitatory and inhibitory receptors utilize distinct post-and trans-synaptic mechanisms in vivo

Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmis¬sion upon binding of the neurotransmitter. Post-and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABAA receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consis¬tent with this finding, ectopic expression at excitatory presynapses of neurexin-3 alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain