Identifying determinants for dendritic compartmentalization and synaptic stabilization of receptors

Yale University, New Haven CT

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Communication between neurons is essential to brain function, and requires the proper localization of neurotransmitter receptors to dedicated synaptic domains within neurons. Indeed, aberrant function/ localization of receptors is implicated in a variety of neurological disorders, including epilepsy, autism, and schizophrenia. Here, I aim to identify novel mechanisms that control receptor localization in neurons, by focusing on the tightly regulated distribution of kainate receptors (KARs) in the brain. Most excitatory transmission in the brain is mediated by ionotropic glutamate receptors (iGluRs), and KARs are a subclass of iGluRs with important roles in synaptic transmission. In the hippocampus, KARs play a pivotal role in signal transmission within the tri-synaptic pathway. Remarkably, KARs are compartmentalized to a very restricted region (stratum lucidum) along the dendrites of CA3 hippocampal neurons, while being excluded from other regions within the same neurons. This highly compartmentalized pattern reflects specific functions for KARs in transmitting mossy fiber pathway input (located in stratum lucidum), while different receptors mediate synaptic transmission originating from other pathways. Revealing the processes that localize KARs in neurons can therefore shed light on mechanisms that shape neuronal function through selective targeting of receptor subtypes into distinct classes of synapses. In this proposal, I will identify the subunits and molecular domains within the KARs protein complex that are critical for dendritic compartmentalization to the stratum lucidum, and for synaptic stabilization of the receptors. This will be done using a combination of molecular biology, biochemistry, cell biology and gene-targeted animals. Successful completion of this work will identify critical components that control neuronal function by localizing the receptors to their correct target. Considering the involvement of KARs in both plasticity and disease, the proposed study will be of high relevance from both translational and basic research perspectives.