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 learning and memory, and will identify synaptic and neural circuit malfunctions that are involved in many neurological and mental disorders, such as Alzheimer's disease, depression and autism disorders. Specifically, during the 2014 fiscal year, we have made following progress:
For research Aim 1 : we have successfully determined the role of GSG1L, a tetraspanning protein that binds to AMPARs in the regulation of excitatory synaptic strength and animal behavior with a combination of electrophysiological, molecular and cellular biological, genetic and behavioral approaches. We found that GSG1L plays a unique and critical role in the negative regulation of AMPAR-mediated synaptic transmission. In addition, GSG1L plays a distinct role in the modulation of AMPAR gating. Finally, we found that the cellular function of GSG1L is important for neural circuit function that underlies object recognition memory in animals. Currently a manuscript for this work has been submitted to a major neuroscience journal for publication.
For research Aim 2 : we have revealed several key molecular processes that are critical for the development of inhibitory synapses. We found that activities of glutamate receptors in developing neurons are crucial for inhibitory synapse development. Current a manuscript for this work has been submitted for publication.
For research Aim 3, we have determined that excitatory synaptic transmission onto principle neurons in the hippocampus is crucial for the maintenance of neuronal inhibition. Specifically, we found that the maintenance of inhibitory inputs originated from Somatostatin-positive, but not Parvalbumin-positive interneurons are sensitive to ongoing excitatory input. Currently we are performing electrophysiological and morphological assays to further characterize the phenomena.
For research Aim 4, we have made significant progress to determine the role of glutamatergic input onto midbrain dopamine neurons. During the 2014 fiscal year, we have systematically performed immunohistochemical and electrophysiological experiments to characterize transgenic/conditional knockout mice in which the majority of glutamatergic input onto midbrain dopamine neurons has been genetically inactivated. Ongoing behavioral studies demonstrate that while glutamatergic input contributes to burst firing of dopamine neurons, it plays an insignificant role in a variety of rewarding behaviors. Currently, we are testing several different rewarding behaviors with these mice, such as conditioned place preference and cocaine-mediated behavioral sensitization. Finally, during the 2014 fiscal year, we have collaborated with Dr. Katherine Roche group at NINDS, NIH to study AMPA receptor trafficking, which resulted in one publication. In addition, we collaborated with Dr. Kent Hamras lab at the University of Texas Southwestern Medical Center in Dallas to generate GSG1L knockout rats to study the role of GSG1L in the regulation of synaptic transmission and animal behavior, which has resulted in a manuscript submitted for publication.

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Hutchison, M A; Gu, X; Adrover, M F et al. (2017) Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior. Mol Psychiatry :
Lu, Wei; Bromley-Coolidge, Samantha; Li, Jun (2017) Regulation of GABAergic synapse development by postsynaptic membrane proteins. Brain Res Bull 129:30-42
Mao, Xia; Gu, Xinglong; Lu, Wei (2017) GSG1L regulates the strength of AMPA receptor-mediated synaptic transmission but not AMPA receptor kinetics in hippocampal dentate granule neurons. J Neurophysiol 117:28-35
Liu, Shuxi; Zhou, Liang; Yuan, Hongjie et al. (2017) A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density. J Neurosci 37:4093-4102
Lu, Wei; Chen, Yelin (2017) Development of fast neurotransmitter synapses: General principle and recent progress. Brain Res Bull 129:1-2
Gu, Xinglong; Zhou, Liang; Lu, Wei (2016) An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development. Cell Rep 14:471-478
Gu, Xinglong; Mao, Xia; Lussier, Marc P et al. (2016) GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons. Nat Commun 7:10873
Lomash, Richa Madan; Gu, Xinglong; Youle, Richard J et al. (2015) Neurolastin, a Dynamin Family GTPase, Regulates Excitatory Synapses and Spine Density. Cell Rep 12:743-51
Lussier, Marc P; Gu, Xinglong; Lu, Wei et al. (2014) Casein kinase 2 phosphorylates GluA1 and regulates its surface expression. Eur J Neurosci 39:1148-58
Lu, Wei; Bushong, Eric A; Shih, Tiffany P et al. (2013) The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. Neuron 78:433-9

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