Synaptic interactions within the thalamus are dynamically regulated in terms of their strength and efficacy. When this dynamic regulation fails to keep synaptic strength in the normal operating range, the thalamocortical circuitry enters a hyper synchronous state that leads to the development of generalized absence seizures. Inhibitory synapses mediated by the neurotransmitter gamma-aminobutyric acid (GABA) play a critical role in regulating synchrony, especially those synapses mediating reciprocal inhibition between thalamic reticular neurons. The long term goals of this project are to understand the pathways that lead to failure of the reciprocal inhibitory circuit and to design interventions that will prevent seizures. In this proposal we will address three major questions relevant to the efficacy of these inhibitory synapses: 1) What are the roles of glial GABA uptake via the transporter GAT-3 and glutamine-dependent GABA cycling in the context of epileptic network oscillations? 2) What is the extent and potency of specific inhibitory connections within the thalamic reticular nucleus? and 3) Can the reciprocal inhibition between thalamic reticular cells be functionally overcome by excitatory corticothalamic and/or thalamocortical synaptic responses? Overall these three questions will address the central theme - synaptic and perisynaptic factors that critically regulate excitability in the reticular nucleus. Our approach will be a combination of whole-cell voltage and current clamp recordings of thalamic neurons in acute rat brain slices, combined with laser scanning photolytic glutamate uncaging, dynamic clamp, genetically-modified mice, and pharmacological manipulation of the GABA neuron-glial transport system. The results of these experiments will provide insight regarding therapeutic approaches that are likely to be effective in the treatment of generalized absence seizures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37NS034774-09
Application #
6826160
Study Section
Special Emphasis Panel (ZRG1-CNNT (01))
Program Officer
Jacobs, Margaret
Project Start
1996-07-22
Project End
2008-06-30
Budget Start
2004-09-01
Budget End
2005-06-30
Support Year
9
Fiscal Year
2004
Total Cost
$333,809
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Paz, Jeanne T; Huguenard, John R (2015) Optogenetics and epilepsy: past, present and future. Epilepsy Curr 15:34-8
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Kyuyoung, Christine L; Huguenard, John R (2014) Modulation of short-term plasticity in the corticothalamic circuit by group III metabotropic glutamate receptors. J Neurosci 34:675-87
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Christian, Catherine A; Huguenard, John R (2013) Sniffer patch laser uncaging response (SPLURgE): an assay of regional differences in allosteric receptor modulation and neurotransmitter clearance. J Neurophysiol 110:1722-31

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