Plates-Formes de Recherche en Neurosciences

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UNIS

Summary

Neurons are morphologically polarized cells constituted by dendritic, somatic and axonal compartments with distinct functions. These compartments contain membrane microdomains (dendritic spines, axonal initial segments, nodes of Ranvier, presynaptic active zones) characterized by specific clusters of receptors and channels that ultimately define the integrative properties and firing patterns of the cell. The electrical phenoptype of the neuron is plastic. Physiologically this property underlies learning and memory storage, but perturbations can result in incapacitating neurological and neuromuscular disease.

Our project focuses on voltage-gated sodium and calcium channels and their role in establishing electrical excitability and triggering neurotransmitter release. However our concepts and aims are dynamic : to understand (i) how trafficking, anchoring, and regulation define the plasticity of neuronal networks thus allowing information processing ; and (ii) how molecular defects that perturb these processes result in channelopathy-associated epilepsy, ataxia and myasthenia. To achieve this project in functional genomics we use a wide range of approaches : protein/protein interactions, neuronal transfection and imaging, patch clamp analysis of plasticity in brain slices. These methods are used to ask specific fundamental questions. What are the intrinsic sequence motifs and trafficking pathways that target channels to axonal microdomains ? How do co-ordinated interactions with regulatory factors and cytoskeletal elements within these domains determine channel clustering and modulation at the plasma membrane ? What are the mechanisms that underlie calcium channel coupling to synaptic vesicle fusion at the active zone ? How do these processes contribute to the long-lasting modifications in intrinsic excitability that constitute a novel means of information storage, complementary to synaptic plasticity. Integrating these methods and concepts to study physiopathology requires the production and analysis of cellular and animal models of neurological disease. These projects will include spinocerebellar ataxia type 6, a neurodegenerative disease associated with polyglutamine expansions in the Cav2.1 channel, and severe myoclonic epilepsy in infancy associated with Nav1.1 channel mutations. Co-ordinated morphological and electrophysiological analysis of the mouse mutant lines med and medJ defective in Nav1.6 expression may provide insights into scapuloperoneal muscular dystrophy and demyelinating disease. Finally using our expertise with surface plasmon resonance protein chip technology we are designing assays for the diagnosis of autoimmune channelopathies and the detection of neuroendocrine marker proteins in tumor biopsies.

In conclusion the “Neurobiology of Ion Channels” laboratory will integrate the concepts and methods of functional genomics to systematically map protein domains, explore their physiological relevance and thus determine how mutations and autoimmune responses result in human neurological disease.

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