The regulation of synaptic transmission and neural circuit function

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

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 and dysfunction in animal behavior and brain illness. We believe that our 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 2022 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 S405 phosphorylation of Shisa7, a new GABA-A receptor auxiliary subunit, in the regulation of GABAergic phasic and tonic inhibition, and neurodevelopmental behavior. A manuscript describing this work has been published in Neuropsychopharmacology. Further, we have characterized the regulation of GABA-A receptors by Shisa7 at the single-channel levels. Currently, a manuscript for this work is under revision in Journal of Neuroscience. Moreover, we have published another work in Cell Reports that showed 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 resubmitted a manuscript to the journal, PLOS Biology, that reports an intriguing inhibitory synaptic plasticity 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, electrophysiological, and behavioral approaches to characterize this new protein. We are in the process of publishing these findings in the near future. For the research Aim 2, during the fiscal year 2022 we have identified a few new compounds that show higher positive allosteric modulator (PAM) activity on GABA-A receptors in complex with Shisa7 in compared to GABA-A receptors on their own. As GABA-A receptors serve as major targets for therapeutic drugs commonly used to treat seizures, pain, mood and sleep disorders, this line of our work indicates important clinical significance in the future. For research Aim 3, 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 and currently we are preparing a manuscript reporting this work. In addition, we have identified a new signaling pathway at GABAergic synapses that regulates NL2 trafficking, GABAergic synapse development and function. We have found that this molecular pathway is disrupted by chronic stress, and importantly, pharmacological rescue of this signaling pathway in stressed animals is able to restore cellular and behavioral defects induced by chronic stress. Currently, we are preparing a manuscript describing these findings. Finally, we have been studying the molecular mechanisms at GABAergic synapses underlying the regulation of alcoholism. Finally, during the 2022 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. Chuan Wu from NCI to study physiology of gut cells, 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 molecules and collaborating with Dr. Angelo Keramidas from Institute for Molecular Bioscience, University of Queensland, to examine the single-channel properties of GABA-A receptors in presence of Shisa7.