The research and training plan will be conducted jointly at the NIH and Johns Hopkins University. The proposed plan contributes to a long term research interest in the physiology of inhibitory synaptic transmission and how it is altered during epileptogenesis, and a long term career goal of building an independent research and clinical program where basic mechanisms of synaptic transmission are applied to the study of epilepsy and the development of new treatment strategies. The ability of inhibitory synapses to maintain their strength and to adapt in response to increased demands will be a central issue in understanding the causes and the treatment of epilepsy. The central hypothesis is that GABA synthesis by inhibitory neurons is regulated by the transport of its precursor, glutamate, into their synaptic terminals, and, as a result, inhibitory transmission is regulated by the release of glutamate from excitatory terminals.
The Specific Aims are to investigate the contribution of neuronal glutamate transporters and other sources of glutamate for GABA synthesis for inhibitory synapses, to examine whether the amount of GABA packaged into vesicles is regulated due to the modulation of glutamate transporters, and to demonstrate whether released glutamate is used to augment GABA release in response to increased or excessive excitation, such as during seizures. It is our expectation that by revealing mechanisms by which GABA synthesis and release are maintained and regulated, we can identify what alterations might contribute to epileptogenesis and where therapeutic interventions could be targeted. To advance the research goals, I will spend 2 years to become skilled in the techniques of synaptic electrophysiology and data analysis with Dr. Jeffrey S. Diamond, an NIH investigator with expertise in the role glutamate transporters in synaptic transmission. In the later years, while continuing my interaction with Dr. Diamond, I will also establish an electrophysiology laboratory at Hopkins. The oversight of my research and career development by Dr. Jeffrey D. Rothstein, who is an expert on the biology glutamate transporters and their role in neurologic disease, will become increasingly important as I make this transition. During the entire time, I will continue to develop my clinical expertise in the treatment of epilepsy at Johns Hopkins, among a group of faculty members with whom I have already worked for several years.
| Stafford, Misty M; Brown, Molly N; Mishra, Puneet et al. (2010) Glutamate spillover augments GABA synthesis and release from axodendritic synapses in rat hippocampus. Hippocampus 20:134-44 |
| Fricke, Molly N; Jones-Davis, Dorothy M; Mathews, Gregory C (2007) Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission. J Neurochem 102:1895-904 |
