Inhibitory neurotransmission is of interest for its role in both disease and therapy. Dysregulated inhibitory neurotransmission is implicated in a broad range of psychiatric diseases, such as schizophrenia, anxiety, and autism. Inhibitory receptors are also the target of diverse drugs, including those with clinical utility (benzodiazepines), abuse potential (ethanol), and lethal toxicity (strychnine). Clinical evidence suggests that defects in one inhibitory ionotropic receptor (glycine receptor, or GlyR) can be compensated by boosting activity in a distinct inhibitory ionotropic receptor (GABAA receptor, or GABAAR). The mechanism underlying this clinical phenomenon is not known, which highlights a key gap in our understanding of inhibitory synapses. Both receptors interact with the putative inhibitory scaffold protein, gephyrin, at synaptic sites, but it is unclear how this interaction impacts receptor localization and function. Two independent questions raised by these observations will be addressed here.
Aim 1 will establish an in-vivo directional link between GABAAR and GlyR synaptic localization using immunohistochemistry and slice electrophysiology.
Aim 2 will reveal the functional impact of gephyrin on GABAAR and GlyR channel properties, surface expression, and assembly in a heterologous system using electrophysiology and biochemistry. A deeper knowledge of the molecular regulation of the inhibitory synapse can change our view of the pathophysiologic basis of devastating psychiatric diseases, and will pave the way for better therapies in the future.

Public Health Relevance

All emergent processes in the brain are mediated by excitatory and inhibitory synaptic transmission. Inhibitory neurotransmission is dysregulated in various diseases (schizophrenia, autism, anxiety), and is the target of various drugs with therapeutic benefits (benzodiazepines) and abuse potential (ethanol). This project will uncover fundamental rules governing receptor activity at the inhibitory synapse, and will lay the groundwork for developing more targeted therapies for these diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH113299-02
Application #
9465234
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Driscoll, Jamie
Project Start
2017-04-01
Project End
2019-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Graduate Schools
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
Martenson, James S; Yamasaki, Tokiwa; Chaudhury, Nashid H et al. (2017) Assembly rules for GABAA receptor complexes in the brain. Elife 6: