The release of neurotransmitters from the presynaptic active zone is a fundamental process that is required for synaptic transmission. Abnormal synaptic transmission underlies various neuropsychiatric diseases such as schizophrenia and depression. Action potential evoked neurotransmitter release is driven by a rise in presynaptic calcium. Calcium-sensing proteins called synaptotagmins bind to calcium and facilitate vesicle fusion. There are two modes of evoked release: fast synchronous release that occurs in phase with the presynaptic action potential and slow asynchronous release which takes place after an action potential has fired. Although synchronous release has been studied extensively, the role of asynchronous release in synaptic transmission is not as well understood. The long-term goal of the proposed study is to elucidate the molecular basis and physiological relevance of asynchronous release. Synaptotagmin-7 (Syt7) has previously been shown in vitro to be the calcium sensor for asynchronous release. The proposed study will utilize Syt7 knockout animals to examine whether Syt7 mediates asynchronous release in vivo, specifically from hippocampal cholecystokinin (CCK)-positive interneurons where asynchronous release is particularly prominent. Behavioral tests will be performed on Syt7 knockout animals to determine whether locomotion, anxiety, social behaviors, and learning and memory are impaired or abnormal. Finally, optogenetic manipulations of hippocampal CCK-positive interneurons will be performed to determine how these neurons specifically modulate an animal's behavior. These experiments will seek to directly link a specific molecular process (Syt7-mediated asynchronous release) in a defined cell type (CCK-interneurons in the hippocampus) to complex animal behaviors (learning and memory).
Neurons release neurotransmitters to transmit signals to other neurons. Abnormal neurotransmission underlie neuropsychiatric diseases such as schizophrenia or depression. Insights into the behavioral output mediated by different modes of neurotransmitter release in defined types of neurons and circuits may lead to new targets and treatments for neuropsychiatric diseases.
|Wu, Dick; Bacaj, Taulant; Morishita, Wade et al. (2017) Postsynaptic synaptotagmins mediate AMPA receptor exocytosis during LTP. Nature 544:316-321|
|Bacaj, Taulant; Wu, Dick; Burré, Jacqueline et al. (2015) Synaptotagmin-1 and -7 Are Redundantly Essential for Maintaining the Capacity of the Readily-Releasable Pool of Synaptic Vesicles. PLoS Biol 13:e1002267|