Role of The Endo/Lysosome System in Synaptic Function

Universidad Andres Bello, Santiago

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Abstract

The endosome/lysosome system (ELS) is an intracellular organization of multiple membranous compartments known to function in protein and lipid trafficking and cellular signaling. Several proteins of the ELS have been associated with the development of neurological disorders. In particular: what is the role the ELS in synaptic transmission and how this system impacts the synapse?s plasticity and its development through age and experience, are basic questions of neurobiology that are not clear. Polymorphisms in the endo/lysosomal protein VAMP7 have been linked with increased Bipolar Disorder susceptibility. Our preliminary findings indicate that VAMP7 deficiency correlates with altered synaptic vesicle pools and neurotransmitter release dynamics at neuronal end terminals. Altogether, our data indicates that although VAMP7 is not crucial for synaptic transmission, it could alter synaptic communication by modifications generated in the ELS. Our principle hypothesize is that VAMP7 alters neuronal communication by disrupting specific ELS functions. To address this hypothesis this project will combine cell imaging with electrophysiology together with classic chemical inhibitors and genetic tools for known proteins that control the trafficking and sorting in the ELS. In Aim 1 we will characterize the pre- and post- synaptic role of VAMP7 in synaptic communication. In Aim 2 we will assess the potential role of VAMP7 in retrograde signaling and synaptic homeostasis. Finally, in Aim3 we will scrutinize the intracellular proteins and pathways that potentially interact with VAMP7 during neuronal activity. This research will contribute to understanding how the ELS regulates the capacity of neurons to communicate and store information. Our proposal will also help elucidate the cellular and molecular pathophysiology of several neurological disorders including Bipolar Disorders, Schizophrenia, and Parkinson, all conditions where components of the ELS are notably altered under situations of cellular stress.