Étude du rôle de l'Hormone de Mélano-Concentration dans la plasticité synaptique (liens possibles entre sommeil et mémoire)

L'Hormone de Mélano-Concentration (MCH) est bien connue chez les mammifères pour son implication dans l'homéostasie énergétique et les comportements alimentaires. Des études récentes ont mis en évidence l'implication de ce neuropeptide hypothalamique dans d'autres fonctions telles que la régulation du sommeil et la mémoire. Ainsi, il a été montré au laboratoire que l'administration de MCH augmente significativement les quantités de sommeil, et plus particulièrement de sommeil paradoxal (SP), un état propice à la consolidation des apprentissages dépendants de l'hippocampe. De plus, les neurones de l'aire hypothalamique latérale synthétisant la MCH sont actifs sélectivement durant cet état et projettent massivement à l'hippocampe, une région où le récepteur à la MCH (MCH-R1) est fortement exprimé. Ces résultats suggèrent que la MCH pourrait jouer son rôle dans les processus de mémorisation par une modulation de la transmission synaptique dans l'hippocampe au cours du SP. Afin de comprendre par quels mécanismes la MCH et le MCH-R1 agissent sur les processus cellulaires de mémorisation, à savoir la plasticité synaptique, nous avons réalisé une étude électrophysiologique in vitro des effets de la MCH dans l'hippocampe du rat et de la souris. En combinant différentes méthodes d'enregistrement et l'utilisation d'animaux transgéniques chez lesquels le gène du MCH-R1 a été invalidé, nous avons mis en évidence de multiples effets induits par la MCH au niveau des synapses entre les collatérales de Schaffer et les cellules pyramidales de CA1. La MCH module la transmission et la plasticité synaptique par des actions pré- et post-synaptiques, et agit sur l'excitabilité neuronale. Ces effets de la MCH au niveau de synapses impliquées dans la consolidation des traces mnésiques dans l'hippocampe pourraient constituer le mécanisme cellulaire sous-tendant le rôle facilitateur du peptide dans la mémoireMelanin-Concentrating Hormone (MCH) is well-known for its implication in energy homeostasis. Recent studies shed light on the role of this neuropeptide in other functions, such as sleep and memory. Administration of MCH has been shown to increase significantly the amounts of paradoxical sleep (PS), which could facilitate the consolidation of some hippocampus-dependent learning tasks. Moreover, MCH-producing hypothalamic neurons are predominantly active during this sleep stage et send axons to the hippocampus, where MCH-R1 receptor is highly expressed. These results suggest that MCH may help memorization by modulating synaptic transmission in hippocampus during PS. We performed the in vitro electrophysiological study of the effects of MCH in the rodent hippocampus to investigate the cellular mechanisms by which MCH and MCH-R1 modulate memory processes. By using different recording techniques and transgenic animal models, we showed that MCH has multiple synaptic effects. MCH modulates synaptic transmission and plasticity by pre- and post-synaptic mechanisms and increases neuronal responsiveness. These MCH effects were found at synapses known to undergo sleep-dependent processes of memory consolidation. These results suggest that MCH may facilitate memory by acting at hippocampal synapsesLYON1-BU.Sciences (692662101) / SudocSudocFranceF

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Major impairments of glutamatergic transmission and long term synaptic plasticity in the hippocampus of mice lacking the melanin-concentrating hormone receptor-1

The hypothalamic neuropeptide melanin-concentrating hormone (MCH) plays important roles in energy homeostasis, anxiety, and sleep regulation. Since the MCH receptor-1 (MCH-R1), the only functional receptor that mediates MCH functions in rodents, facilitates behavioral performance in hippocampus-dependent learning tasks, we investigated whether glutamatergic transmission in CA1 pyramidal cells could be modulated in mice lacking the MCH-R1 gene (MCH-R1(-/-)). We found that both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor-mediated transmissions were diminished in the mutant mice compared with their controls. This deficit was explained, at least in part, by a postsynaptic down-regulation of these receptors since the amplitude of miniature excitatory postsynaptic currents and the NMDA/AMPA ratio were decreased. Long-term synaptic potentiation (LTP) was also impaired in MCH-R1(-/-) mice. This was due to an altered induction, rather than an impaired, expression because repeating the induction stimulus restored LTP to a normal magnitude. In addition, long-term synaptic depression was strongly diminished in MCH-R1(-/-) mice. These results suggest that MCH exerts a facilitatory effect on CA1 glutamatergic synaptic transmission and long-term synaptic plasticity. Recently, it has been shown that MCH neurons fire exclusively during sleep and mainly during rapid eye movement sleep. Thus these findings provide a mechanism by which sleep might facilitate memory consolidation

Microtubule stabilizer ameliorates synaptic function and behavior in a mouse model for schizophrenia.

International audienceBACKGROUND: Recent data suggest that cytoskeletal defects may play a role in schizophrenia. We previously imitated features of schizophrenia in an animal model by disrupting gene coding for a microtubule-associated protein called STOP. STOP-null mice display synaptic defects in glutamatergic neurons, hyper-dopaminergy, and severe behavioral disorders. Synaptic and behavioral deficits are amended by neuroleptic treatment in STOP-null mice, providing an attractive model to test new antipsychotic agents. We examined the effects of a taxol-related microtubule stabilizer, epothilone D. METHODS: Mice were treated either with vehicle alone or with epothilone D. Treatment effects on synaptic function were assessed using electron-microscopy quantification of synaptic vesicle pools and electrophysiology in the CA1 region of the hippocampus. Dopamine transmission was investigated using electrochemical assays. Behavior was principally assessed using tests of maternal skills. RESULTS: In STOP-null mice, treatment with epothilone D increased synaptic vesicle pools, ameliorated both short- and long-term forms of synaptic plasticity in glutamatergic neurons, and had a dramatic beneficial effect on mouse behavior. CONCLUSIONS: A microtubule stabilizer can have a beneficial effect on synaptic function and behavior, suggesting new possibilities for treatment of schizophrenia