The regulation of synaptic transmission and neural circuit function

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

The lab is interested in understanding molecular and cellular mechanisms underlying synapse formation and synaptic plasticity, and in the long term elucidating synaptic mechanisms underlying neuronal circuit function in animal behavior. We believe that these studies will provide fundamental insights into neural underpinnings for brain cognition and will help identify synaptic and neural circuit malfunctions that are involved in many neurological and mental disorders, such as epilepsy, Alzheimer's disease, depression and autism. Specifically, during the 2021 fiscal year, we have made following progress: For research Aim 1, which focuses on identifying and characterizing novel proteins that bind to GABA-A receptors and/or that regulate inhibitory transmission, we have identified an important role of Shisa7, a new GABA-A receptor auxiliary subunit, in the regulation of GABAergic tonic inhibition. A manuscript describing this work has been published in Cell Reports. We have also revealed a critical role of Shisa7 phosphorylation at S405 in inhibitory transmission, synaptic plasticity and neurodevelopmental behavior. Further, we have characterized the regulation of GABA-A receptors by Shisa7 at the single-channel levels. Moreover, we have discovered a differential role of NMDAR subunits in the regulation of tonic inhibition in hippocampal neurons and how such regulation may be involved in ischemic stroke. Furthermore, we have found an intriguing inhibitory synaptic plasticity that is regulated by the daily wake-sleep cycle. Finally, we have identified a new transmembrane protein that binds to GABA-A receptors and regulates inhibitory transmission. Currently we are using genetic, imaging, electrophysiology and behavioral approaches to characterize this new protein. We are in the process of publishing these findings. For research Aim 2, we investigate the mechanisms for the regulation of GABAergic synapse development and function in health and disease. We have made important progress in determining the molecular and cellular mechanisms underlying GABAergic synapse development. Specifically, we have determined how trans-synaptic cell adhesion interactions regulate GABAergic synapse development. In addition, we have identified new molecules mediating NMDAR-dependent signaling for GABAergic synaptogenesis, revealed how key inhibitory synaptic proteins important for synapse formation are transported to synapses during development, and provided key evidence for how the regulation of GABAergic synapse development is involved in stress processes in the brain. We plan to submit two manuscripts describing these findings Finally, during the 2021 fiscal year, we have collaborated with Dr. Katherine Roche group at NINDS, NIH to study Neuroligins. We have also collaborated with Dr. Yan Li from NINDS, NIH to characterize neuronal GABA-A receptors complexes, Dr. Joe Steiner from NINDS, NIH to screen new compounds targeting the GABA-A receptor/Shisa7 complex, Dr. Susan Cheng from NINDS, NIH to use the EM approach to characterize GABAergic synapses, and Dr. Lijin Dong from NEI, NIH to generate a novel mouse line for our research projects. We are also collaborating with Dr. Henry Houlden group at University of College London, UK to study human mutations in Slitrk3, an inhibitory synaptic adhesion molecule, and Dr. Steven Hou from Fudan University, China to study the role of Arf1 in neurodegeneration.