The issue of what starts and stops individual epileptic seizures is a topic of intense interest and investigation. Brain dynamics can rapidly cycle between a state supporting normal, physiological activity and an epileptic state characterized by uncontrolled and intense, usually oscillatory activity. This is especially the situation for generalized absence epilepsy, in which individual seizures occur suddenly and briefly interrupt behavior for perhaps a few seconds, and then just as suddenly terminate to allow resumption of normal activity. The thalamocortical system is involved in these transitions in absence epilepsy, with the thalamic reticular nucleus and its inhibitory output playing an essential role. It has recently been shown that derangements in excitatory connectivity from cortex or thalamus to the thalamic reticular nucleus can lead to experimental absence seizures. The proposed studies will examine the response dynamics of reticular neurons in a variety of conditions that mimic the beginning, middle and end of seizures. Experiments will involve photostimulation of axons via virally delivered genetically encoded opsins that will allow specific and simultaneous interrogation of thalamic and/or cortical pathways. Using whole cell voltage- and current-clamp recordings from thalamic neurons in brain slices, experiments will determine the patterns of cortical inputs that dynamically switch the thalamic subcircuit into seizure generating mode, and determine how interactions between cortical and thalamic inputs sustain and propagate the seizures. Studies will examine activity dependent changes in synapse efficacy mediated by the metabotropic glutamate receptor mGluR7a, which has been shown to play a role in absence seizure regulation. Finally, experiments will determine the excitatory conditions under which the normally protective interconnections between reticular neurons break down leading to seizure onset. The results of these studies will lead to an understanding of brain dynamics in absence epilepsy and guide development of new therapies.

Public Health Relevance

Patients with epilepsy have the unique challenge of dealing with the unpredictable nature of their seizures. The exact time that each seizure will occur is unknown as is how long each seizure will last. The proposed research will determine the events in the central nervous system that lead up to seizures, especially in childhood absence epilepsy, with the ultimate hope that improved seizure therapies can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034774-17
Application #
8320866
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
1996-07-22
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
17
Fiscal Year
2012
Total Cost
$347,498
Indirect Cost
$128,748
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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Ha, Huong; Huguenard, John (2016) Criminal Minds: Cav3.2 Channels Are the Culprits, but NMDAR Are the Co-Conspirators. Epilepsy Curr 16:36-8
Paz, Jeanne T; Huguenard, John R (2015) Optogenetics and epilepsy: past, present and future. Epilepsy Curr 15:34-8
Farzampour, Zoya; Huguenard, John (2015) Seizing upon mechanisms for impaired consciousness. Neuron 85:453-5
Farzampour, Zoya; Reimer, Richard J; Huguenard, John (2015) Endozepines. Adv Pharmacol 72:147-64
Ma, Yunyong; Juntti, Scott A; Hu, Caroline K et al. (2015) Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish. Proc Natl Acad Sci U S A 112:3805-10
Makinson, Christopher D; Huguenard, John R (2015) Attentional flexibility in the thalamus: now we're getting SOMwhere. Nat Neurosci 18:2-4

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