GABAergic synapses are the major inhibitory connections in the brain and likely play an important role in all brain functions, including learning and memory. A deficit in GABAergic synapses is often implicated in devastating disorders such as autism, schizophrenia, and epilepsy. Despite their importance, many fundamental questions regarding the regulation and function of GABAergic synapses remain unanswered. Our long-term goal is to explore the cellular and molecular mechanisms by which neuronal activity is coupled to modification of GABAergic synapses during behavioral experience and to understand how disruption of this form of GABAergic synaptic plasticity leads to cognitive deficits. Towards this goal, we have recently identified the activity-regulated bHLH-PAS transcription factor Npas4 as a key regulator of GABAergic synapses. Npas4 is rapidly induced by excitatory synaptic activity and its level determines the number of GABAergic synapses formed on excitatory neurons. These findings suggest that Npas4 is the molecular link between neuronal excitation and GABAergic synapses. By investigating Npas4's role in regulating activity-dependent modulation of GABAergic synapses and regulating behavioral output of neural circuits, the research plan outlined here will yield new insights into the etiology of many neurological disorders.

Public Health Relevance

The research described in this proposal will explore the role of GABAergic synaptic plasticity in important neural circuit functions such as learning and memory. A deficit in GABAergic synapses is often implicated in devastating neurological disorders such as autism, schizophrenia, and epilepsy, most of which often involve profound psychiatric and cognitive deficits in afflicted individuals. Our proposed study will shed light on the pathology and etiology of these neurological diseases.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01MH091220-05
Application #
8644909
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Asanuma, Chiiko
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
None
Type
Organized Research Units
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Chuong, Amy S; Miri, Mitra L; Busskamp, Volker et al. (2014) Noninvasive optical inhibition with a red-shifted microbial rhodopsin. Nat Neurosci 17:1123-9
Ramamoorthi, Kartik; Lin, Yingxi (2011) The contribution of GABAergic dysfunction to neurodevelopmental disorders. Trends Mol Med 17:452-62
Ramamoorthi, Kartik; Fropf, Robin; Belfort, Gabriel M et al. (2011) Npas4 regulates a transcriptional program in CA3 required for contextual memory formation. Science 334:1669-75