The proper function of neurotransmitters receptors is highly dependent on their precise subcellular localization in neurons. The molecular and cellular mechanisms that govern the synaptic localization of glutamate receptors both depend on the molecular structure of receptors and on interactions with cytoplasmic and extracellular proteins. These mechanisms have been widely studied using a variety of techniques applied to nonneuronal cells and to dissociated neurons in cultures. In contrast, our aim is to approach this question in an experimental situation which approximates polarized trafficking of receptors in an in vivo situation. Excitatory synaptic transmission in the mammalian brain is primarily mediated by ionotropic glutamate receptors (iGluRs) which fall into three classes: AMPA, NMDA and KARs. These ligand gated ion channels share common architecture, but display divergent functions. Kainate receptors have recently appeared to play an important role in the regulation of the activity of synaptic networks. Kainate receptors are involved in synaptic integration, in synaptic plasticity, in the regulation of neurotransmitter release and in the control of neuronal excitability. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We will study the mechanisms that account for the highly restricted localization of kainate receptors (KARs) in the proximal dendrites of hippocampal CA3 pyramidal cells, at mossy fiber (MF) synapses. For this purpose, we will take advantage of a multidisciplinary integrated approach combining molecular and cellular tools (transgenic mice, organotypic cultures, biolistic transfection) with electrophysiological and imaging techniques.
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