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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Whittemore, Vicky R
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Stanford University
Schools of Medicine
United States
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Goddard, C Alex; Mysore, Shreesh P; Bryant, Astra S et al. (2014) Spatially reciprocal inhibition of inhibition within a stimulus selection network in the avian midbrain. PLoS One 9:e85865
Goddard, C Alex; Huguenard, John; Knudsen, Eric (2014) Parallel midbrain microcircuits perform independent temporal transformations. J Neurosci 34:8130-8
Mattis, Joanna; Brill, Julia; Evans, Suzanne et al. (2014) Frequency-dependent, cell type-divergent signaling in the hippocamposeptal projection. J Neurosci 34:11769-80
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
Dewolfe, Jennifer L; Malow, Beth; Huguenard, John et al. (2013) Sleep and epilepsy: a summary of the 2011 merritt-putnam symposium. Epilepsy Curr 13:42-9
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
Christian, Catherine A; Herbert, Anne G; Holt, Rebecca L et al. (2013) Endogenous positive allosteric modulation of GABA(A) receptors by diazepam binding inhibitor. Neuron 78:1063-74
Ma, Yunyong; Huguenard, John R (2013) Reemerging role of cable properties in action potential initiation. Proc Natl Acad Sci U S A 110:3715-6
Paz, Jeanne T; Davidson, Thomas J; Frechette, Eric S et al. (2013) Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci 16:64-70
Zhang, Wei; Huguenard, John R; Buckmaster, Paul S (2012) Increased excitatory synaptic input to granule cells from hilar and CA3 regions in a rat model of temporal lobe epilepsy. J Neurosci 32:1183-96

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