3-aminobutyric acid (GABAA) receptors are the major sites of synaptic inhibition in the CNS and are drug targets for a variety of pharmacotherapeutic agents such as benzodiazepines, barbiturates, general anesthetics and neurosteroids. Compromised GABAergic transmission is one of the contributing factors in a number of neurological and psychiatric diseases such as epilepsy, anxiety, sleep disorders, addiction, autism, mental retardation, depression and schizophrenia. The number of post-synaptic GABAA receptors is highly regulated and is a major determinant in modulating the strength of synaptic inhibition. Chronic bi-directional changes in neuronal activity can lead to global, compensatory adjustments in excitatory and inhibitory synaptic strengths;a process known as homeostatic synaptic scaling. Modulating the number of GABAA receptors at post-synaptic sites is one of the mechanisms underlying activity dependent changes in inhibitory synaptic transmission. I have previously shown that chronic changes in neuronal activity regulate the endoplasmic reticulum (ER)-associated degradation of GABAA receptors, mediated by Ca2+ influx through L-type voltage gated Ca2+channels, modulating receptor cell surface number and efficacy of synaptic inhibition. However, the signaling pathways linking changes in neuronal activity to the modulation of GABAA receptor turnover and abundance at inhibitory synapses is unknown. These phenomena together with my preliminary studies have allowed me to generate a central hypothesis driving the experiments in this proposal: Activity dependent phosphorylation of the GABAA receptor ?3 subunit on serine 383 by CaMKII, modulates the insertion of these receptors and consequently their abundance at inhibitory synapses, modifying the efficacy of synaptic inhibition. My work will focus on 3 distinguishable but complimentary experimental goals: 1) To test the hypothesis that the CaMKII phosphorylation site within the GABAA receptor ?3 subunit (S383) modulates the synaptic expression levels of these receptors and synaptic inhibition. 2) To test the hypothesis that changes in [Ca2+]i regulate the CaMKII dependent phosphorylation of ?3S383 and the numbers of GABAA receptors at the cell surface. 3) To test the hypothesis that changes in neuronal activity modulate the CaMKII phosphorylation of ?3S383 and regulates the insertion and abundance of cell surface GABAA receptors.

Public Health Relevance

Neurotransmitters can either excite or inhibit the activity of neurons, and GABA is the main inhibitory neurotransmitter in the brain while glutamate is an excitatory neurotransmitter. GABA binds to the GABAA receptor, which then opens and allows negatively charged ions into the neuron, inhibiting its electrical activity. Altering the numbers of GABAA receptors on the surface of a neuron modulates its electrical activity, and understanding how neurons regulate the numbers of GABAA receptors is important for understanding a number of brain diseases like epilepsy and Schizophrenia, where electrical activity is deregulated and the number of GABAA receptors is altered.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Research Grants (R03)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Nadler, Laurie S
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Tufts University
Schools of Medicine
United States
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Saliba, Richard S; Kretschmannova, Karla; Moss, Stephen J (2012) Activity-dependent phosphorylation of GABAA receptors regulates receptor insertion and tonic current. EMBO J 31:2937-51