The development of excitatory and inhibitory circuits in the neocortex is critical for establishing normal patterns of brain activity, and dysregulation of this process may contribute to a number of neuropsychiatric disorders, including schizophrenia and autism. However, the organization and regulation of inhibitory synaptogenesis during early development remain poorly understood. This lack of knowledge is due, in part, to heterogeneity in GABAergic circuits and the absence of appropriate tools for dissecting the contribution of different IN populations to early GABAergic signaling. In the present study, we utilize a combination to electrophysiology, optogenetics, 2-photon imaging and uncaging, and fluorescent labeling of GABAergic synapses to (1) elaborate the development of functional inhibitory inputs to pyramidal neuron (PN) dendrites, (2) reveal novel mechanisms for circuit-specific GABAergic plasticity, and (3) elucidate the interactions of glutamatergic and GABAergic signaling in the normal wiring of cortical circuits. Our overall goal is to understand the links between excitatory and inhibitory signaling that operate during development and maintain cortical circuit function. We expect that our results will generate new avenues for exploring both the cell biology of GABAergic function and the general mechanisms by which the brain develops and adapts to experience.

Public Health Relevance

This proposal seeks to understand the functional development of inhibitory GABAergic synapses in the prefrontal cortex. Results from these studies will help identify novel mechanisms by which the brain is wired during development and in response to experience. We further expect our findings to provide important insights into the cellular underpinnings of neurodevelopmental disorders such as autism and schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099045-07
Application #
9598632
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kim, Douglas S
Project Start
2012-09-20
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Chang, Jeremy T; Higley, Michael J (2018) Potassium channels contribute to activity-dependent regulation of dendritic inhibition. Physiol Rep 6:e13747
Batista-Brito, Renata; Vinck, Martin; Ferguson, Katie A et al. (2017) Developmental Dysfunction of VIP Interneurons Impairs Cortical Circuits. Neuron 95:884-895.e9
Xiao, Xiao; Levy, Aaron D; Rosenberg, Brian J et al. (2016) Disruption of Coordinated Presynaptic and Postsynaptic Maturation Underlies the Defects in Hippocampal Synapse Stability and Plasticity in Abl2/Arg-Deficient Mice. J Neurosci 36:6778-91
Kannan, Madhuvanthi; Gross, Garrett G; Arnold, Don B et al. (2016) Visual Deprivation During the Critical Period Enhances Layer 2/3 GABAergic Inhibition in Mouse V1. J Neurosci 36:5914-9
Lur, Gyorgy; Vinck, Martin A; Tang, Lan et al. (2016) Projection-Specific Visual Feature Encoding by Layer 5 Cortical Subnetworks. Cell Rep 14:2538-45
Lur, Gyorgy; Higley, Michael J (2015) Glutamate Receptor Modulation Is Restricted to Synaptic Microdomains. Cell Rep 12:326-34
Gamo, Nao J; Lur, Gyorgy; Higley, Michael J et al. (2015) Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. Biol Psychiatry 78:860-70
Higley, Michael J (2014) Localized GABAergic inhibition of dendritic Ca(2+) signalling. Nat Rev Neurosci 15:567-72
Amatrudo, Joseph M; Olson, Jeremy P; Lur, G et al. (2014) Wavelength-selective one- and two-photon uncaging of GABA. ACS Chem Neurosci 5:64-70

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