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.
Bipolar Affective Disorder (BPAD) and Schizophrenia are severe mental disorders that affect the life quality of 60 million people worldwide, yet the cellular mechanisms that are altered in such mental disorders are not clear. Several studies indicate that alterations in genes that function in the Endo/Lysosomal System (ELS) result in elevated susceptibility for such mental disorders. A specific example, is the ELS protein VAMP7, which has been detected in genetic screens in humans with a heritable form of BPAD, suggesting that the downregulation of VAMP7 could be relevant in BPAD susceptibility. Hence, elucidating the cellular pathophysiology of endosome and lysosome dysfunction may help in understanding BPAD development. We have generated a Drosophila model system which impairs VAMP7 expression. Our preliminary work indicates that VAMP7 deficiency alters synaptic transmission, short-term memory and lifespan. Given VAMP7 established role in endosome function, this application will define the defects in synaptic function present in a Drosophila model system with the ELS dysfunction via VAMP7 deficiency. This project will contribute in dissecting the regulatory pathways of neuronal communication in the context of endo/lysosome function. The results will elucidate how the ELS regulates synaptic transmission and enhance our understanding of the cellular basis for neuronal communication and its impairment in the mentioned mental disorders.
