Chronic epilepsy results in large measure from reorganization of cortical circuits in a manner that promotes excessive excitatory interactions among neurons. In this project, we will use several approaches to address questions related to the theme of """"""""What are the mechanisms that underlie the increased excitatory connectivity in the epileptic brain?"""""""" In Project 1, the program director, David Prince, will study alterations in inhibitory mechanisms, including changes in the synaptic innervation of inhibitory inter-neurons, and possible decreases in inhibition due to known reductions in a potassium/chloride co-transporter in pyramidal cells. He will also investigate mechanisms of increased excitatory synaptic connectivity in layer V of rat neocortex in the partially-isolated cortical island model of chronic epilepsy. In Project II, John Huguenard will examine the role of a particular subtype of excitatory neurotransmitter receptor, that containing the GluR2 subunit, in normal cortical synaptic function, and the results of its loss in pyramidal neurons of chronic epileptic neocortical circuits. GluR2 is down-regulated in human epilepsy and in animal models of the disease, and he will test the hypothesis that this maladaptive change, which in some ways recapitulates ontogeny, alters synaptic responses in a way that would contribute to epileptogenesis. In Project III, Paul Buckmaster will investigate alterations in connectivity of entorhinal cortex in the well-established post-pilocarpine model of chronic temporal lobe epilepsy. He will test the hypothesis that layer-specific cell loss, known to occur in this cortex, gives rise to decreased inhibitory synaptic control of principal neurons, and that increases in recurrent excitatory connectivity result in a hypersynchronous output that drives the dentate gyrus. A Core section will provide neuroanatomical, computer, mechanical and administrative support. Experiments will employ state-of-the-art techniques, such as laser-scanning caged-glutamate mapping, whole-cell recordings of unitary synaptic responses, local perfusion of discrete synaptic regions in slices to identify injury-dependent synaptic receptor reorganization, and anatomical techniques, including immunocytochemistry, in situ hybridization, confocal and deconvolution microscopy, and computer-assisted quantification of neuronal structure. Collaborations are an integral part of this project, and the expected result is a greatly enhanced understanding of the role played by functional synaptic reorganization in epileptogenesis, with the ultimate hope that approaches may someday be available to inhibit the maladaptive reorganization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS012151-28
Application #
6616131
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fureman, Brandy E
Project Start
1975-06-01
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
28
Fiscal Year
2003
Total Cost
$1,120,952
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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Takahashi, D Koji; Gu, Feng; Parada, Isabel et al. (2016) Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma. Neurobiol Dis 91:166-81
Prince, David A (2014) How do we make models that are useful in understanding partial epilepsies? Adv Exp Med Biol 813:233-41
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Jin, Xiaoming; Jiang, Kewen; Prince, David A (2014) Excitatory and inhibitory synaptic connectivity to layer V fast-spiking interneurons in the freeze lesion model of cortical microgyria. J Neurophysiol 112:1703-13
Mantoan Ritter, Laura; Golshani, Peyman; Takahashi, Koji et al. (2014) WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis. Epilepsia 55:1693-702
Dulla, C G; Tani, H; Brill, J et al. (2013) Glutamate biosensor imaging reveals dysregulation of glutamatergic pathways in a model of developmental cortical malformation. Neurobiol Dis 49:232-46
Ma, Yunyong; Ramachandran, Anu; Ford, Naomi et al. (2013) Remodeling of dendrites and spines in the C1q knockout model of genetic epilepsy. Epilepsia 54:1232-9
Carter, Matthew E; Brill, Julia; Bonnavion, Patricia et al. (2012) Mechanism for Hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci U S A 109:E2635-44
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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