Epilepsy is a devastating condition with no cure as yet, and many patients suffer from seizures that are resistant to current treatment options. Many changes in the brain occur during epileptogenesis, but it has been difficult to distinguish those that are directly pathological from those that are merely compensatory. This complexity presents a major obstacle in identifying novel therapeutic targets. One potential target is the GABAA receptor ? subunit, which mediates tonic inhibition in many brain regions. The expression of this subunit decreases in principal neurons in the hippocampus during epileptogenesis, but the interpretation of this change is uncertain because it is not understood why the brain utilizes two forms of inhibition, tonic and phasic. This project utilizes a novel conditional-knockout mouse line to selectively examine the function of tonic versus phasic inhibition. By dissociating the two types of inhibition, we will uncover the role of tonic inhibition in normal hippocampal function as well as under pathological conditions, such as epileptogenesis. This proposal employs a multifaceted approach, from the examining the role of tonic inhibition in individual neurons to an entire network of neurons, to animal behavior and in vivo models of epileptogenesis. The results will provide information as to the role of tonic inhibition in the CNS as well as to evaluate the potential of these receptors in the development of new treatments for epilepsy.

Public Health Relevance

This project will dissect out the specific role of tonic versus phasic GABAergic inhibition with the goal of understanding the specific function and, thus, the necessity for two distinct forms of inhibition. We will determine the contribution of these two forms of inhibition to normal network function and epileptogenesis.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Neurological Sciences Training Initial Review Group (NST)
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Whittemore, Vicky R
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Tufts University
Schools of Medicine
United States
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Lee, Vallent; MacKenzie, Georgina; Hooper, Andrew et al. (2016) Reduced tonic inhibition in the dentate gyrus contributes to chronic stress-induced impairments in learning and memory. Hippocampus 26:1276-1290
Lee, Vallent; Maguire, Jamie (2014) The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits 8:3
Lee, Vallent; Sarkar, Jhimly; Maguire, Jamie (2014) Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors. Psychoneuroendocrinology 41:75-88
Lee, Vallent; Maguire, Jamie (2013) Impact of inhibitory constraint of interneurons on neuronal excitability. J Neurophysiol 110:2520-35