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Séminaire impromptu - Cécile BatsRole of TARPs in the trafficking of calcium-permeable AMPA receptors: functional evidence from stargazer cerebellar neurons

Abstract :

Invitation de Daniel Choquet

Most fast excitatory synaptic transmission in the central nervous system is mediated by AMPA receptors (AMPARs). AMPARs are tetramers formed from various combinations of the four subunits GluA1-4. AMPARs are cation-permeable channels that cause membrane depolarization upon glutamate binding. The vast majority of native AMPAR complexes contain GluA2, which renders the channel impermeable to calcium (calcium-impermeable CI-AMPARs). While less widely expressed, GluA2-lacking calcium-permeable AMPARs (CP-AMPARs) are essential to normal brain development and to synaptic transmission and plasticity in a variety of mature neuronal and glial cells. Upregulation or overactivation of such CP-AMPARs however can be detrimental, and has been linked to a range of neurological disorders including hypoxic/ischemic damage, chronic pain and drug addiction. Therefore, understanding the molecular mechanisms involved the control of CP-AMPAR expression is fundamental. In recent years, we have been investigating the involvement of transmembrane AMPA receptor regulatory proteins (TARPs) in the differential trafficking of CI- and CP-AMPARs.
 
TARPs were originally discovered in stargazer mice. These spontaneous mutants, which lack stargazin (one of the seven known TARP isoforms), display an abnormal motor behavior due to the absence of surface AMPARs in cerebellar granule cells. Since this initial observation, our view of AMPARs has been dramatically changed, and TARPs are now considered to be key elements of native AMPAR complexes throughout the brain, enhancing their expression and conductance. Yet, most of this evidence was obtained in neurons that lack CP-AMPARs.
 
Using patch-clamp techniques, we studied the effect of the stargazer mutation on the composition and distribution of AMPARs in cerebellar stellate cells. We focused our investigations on these neurons as they are quite similar to cerebellar granule cells in respect to their TARP content but they express a significant population of CP-AMPARs which play an important role in their physiology. The results of these experiments were surprising and indicate that the interplay between AMPARs and TARPs is more complex than initially thought.

Focus



Cécile Bats a soutenu sa thèse en  Nov 2006 à Bordeaux sous la direction de Daniel Choquet dans le Laboratoire de "Physiologie cellulaire de la synapse "Titre : Etude du rôle des protéines d’échafaudage dans le contrôle du trafic de surface des récepteurs AMPA . Elle  est actuellement en poste au : Department of Neuroscience, Physiology & Pharmacology, University College London, United Kingdom.