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Perroy, J.

Publications and source records attributed to Perroy, J..

5 recordsLinked to original sources

Mice adapt their learning rate to stochasticity and volatility through a simple heuristic

Learning from outcomes requires weighing each surprise by how much it is likely to mean. Two properties of the environment set that weight in opposite directions: volatility, the rate at which contingencies change, and stochasticity, the noise in outcomes around a stable contingency. Whether animals separate the two is unresolved, in part because varying reward probability in a reversal task makes outcomes noisier and the two options harder to tell apart at once. We trained male and female mice on a probabilistic reversal task for intracranial self-stimulation, scaling reward magnitude with reward probability so that the expected reward of each option and the difference between them stayed constant while outcome variance varied, and crossing this with different reversal rates. Simulations show that adapting the learning rate alone and adapting the decision policy alone are near-equivalent solutions across the environments we tested. Mice adopted the first adjustment: their fitted learning rate rose with volatility and fell with stochasticity, in both directions predicted by reward maximization, while their inverse temperature stayed fixed. This joint dependence was reproduced only by a meta-learning rule that reads stochasticity from the size of prediction errors and volatility from how often recent outcomes favored switching

neuroscience↗

Voltage tunes mGlu5 receptor function, impacting synaptic transmission

Voltage sensitivity is a common feature of many membrane proteins, including some G-protein coupled receptors (GPCRs). However, the functional consequences of voltage sensitivity in GPCRs are not well understood. In this study, we investigated the voltage sensitivity of the post-synaptic metabotropic glutamate receptor mGlu5 and its impact on synaptic transmission. Using biosensors and electrophysiological recordings in non-excitable HEK293T cells or neurons, we found that mGlu5 receptor function is optimal at resting membrane potentials. We observed that membrane depolarization significantly reduced mGlu5 receptor activation, Gq-PLC/PKC stimulation, Ca2+ release, and mGlu5 receptor-gated currents through TRPC6 channels or NMDA receptors. Notably, we report a previously unknown activity of the NMDA receptor at the resting potential of neurons, enabled by mGlu5. Our findings suggest that mGlu5 receptor activity is directly regulated by membrane voltage which may have a significant impact on synaptic processes and pathophysiological functions.

neuroscience↗

Modulation of hippocampal network oscillation by PICK1-dependent cell surface expression of mGlu3 receptors

mGlu3 receptors control the sleep/wake architecture which plays a role in the glutamatergic pathophysiology of schizophrenia. Interestingly, mGlu3 receptors expression is decreased in the brain of schizophrenic patients. However, little is known about the molecular mechanisms regulating mGlu3 receptors at the cell membrane. Subcellular receptor localization is strongly dependent on proteinprotein interactions. Here we show that mGlu3 interacts with PICK1 and that their binding is important for receptor surface expression and function. Disruption of their interaction via an mGlu3 C-terminal mimicking peptide or an inhibitor of the PDZ domain of PICK1 altered the functional expression of mGlu3 receptors. Consequently, we investigated whether disruption of the mGlu3-PICK1 interaction affects hippocampal theta oscillations in vitro and in vivo. We found a decreased frequency of theta oscillations in organotypic hippocampal slices, similar to what previously observed in mGlu3 -/- mice. In addition, hippocampal theta power was reduced during REM sleep, NREM sleep and wake states after intra-ventricular administration of the mGlu3 C-terminal mimicking peptide. Targeting the mGlu3-PICK1 complex could thus be relevant to the pathophysiology of schizophrenia.

neuroscience↗

Restoring Glutamate receptosome dynamics at synapses rescues Autism-like deficits in Shank3-deficient mice.

Shank3 monogenic mutations lead to Autism Spectrum Disorders (ASD). Shank3 is part of the glutamate receptosome that physically links ionotropic NMDA receptors to metabotropic mGlu5 receptors through interactions with scaffolding proteins PSD95-GKAP-Shank3-Homer. A main physiological function of the glutamate receptosome is to control NMDA synaptic function that is required for plasticity induction. Intact glutamate receptosome supports glutamate receptors activation and plasticity induction, while glutamate receptosome disruption blocks receptors activity, preventing the induction of subsequent plasticity. Despite possible impact on metaplasticity and cognitive behaviors, scaffold interaction dynamics and their consequences are poorly defined. Here we used mGlu5-Homer interaction as a biosensor of glutamate receptosome integrity to report changes of NMDA synaptic function. Combining BRET imaging and electrophysiology, we show that a transient neuronal depolarization inducing NMDA-dependent plasticity disrupts glutamate receptosome in a long-lasting manner at synapses and induces signaling required for the expression of the initiated neuronal plasticity such as ERK and mTOR pathways. Glutamate receptosome disruption also decreases NMDA/AMPA currents ratio, freezing the sensitivity of the synapse to subsequent changes of neuronal activity. These data show the importance of a fine-tuning of protein-protein interactions within glutamate receptosome, driven by changes of neuronal activity, to control plasticity. In a mouse model of ASD, a truncated mutant form of Shank3 prevents the integrity of the glutamate receptosome. These mice display altered plasticity, anxiety-like and stereotyped behaviors. Interestingly, repairing the integrity of glutamate receptosome and its sensitivity to the neuronal activity rescued synaptic transmission, plasticity and some behavioral traits of Shank3{triangleup}C mice. Altogether, our findings characterize mechanisms by which Shank3 mutations cause ASD and highlight scaffold dynamics as new therapeutic target.

neuroscience↗

The mGlu7 receptor provides protective effects against epileptogenesis and epileptic seizures

Finding new targets to control or reduce seizure activity is essential to improve the management of epileptic patients. We hypothesized that activation of the pre-synaptic and inhibitory metabotropic glutamate receptor type 7 (mGlu7) reduces spontaneous seizures. We tested LSP2-9166, a recently developed mGlu7/4 agonist with unprecedented potency on mGlu7 receptors, in two paradigms of epileptogenesis. In a model of chemically induced epileptogenesis (pentylenetetrazol systemic injection), LSP2-9166 induces an antiepileptogenic effect rarely observed in preclinical studies. In particular, we found a bidirectional modulation of seizure progression by mGlu4 and mGlu7 receptors, the latter preventing kindling. In the intra-hippocampal injection of kainic acid mouse model that mimics the human mesial temporal lobe epilepsy, we found LSP2-9166 reduced seizure frequency and hippocampal sclerosis. LSP2-9166 also acts as an anti epileptic drug on established seizures in both models tested. Specific modulation of the mGlu7 receptor could represent a novel approach to reduce pathological network remodeling.

neuroscience↗