Epilepsy is a neurological disorder afflicting nearly 3 million patients in this country alone. It is thought to arise through reorganization of neural circuitry often following injury. However those aspects of reorganization that are adaptive, and will prevent the eventual development of epilepsy, vs those that are maladaptive and will lead to epileptogenesis, remain unclear. This program brings together the expertise of 3 investigators into a collaborative team that will address different aspects of circuit reorganization relevant to epileptogenesis. In project 1, David Prince, will determine whether down regulation of ATPase in inhibitory axons and terminals of injured, undercut cortex leads to defects in synaptic inhibition and whether basket cells, a major class of inhibitory neurons, become functionally deafferented from their postsynaptic targets. In project 2, John Huguenard will use the freeze lesion model of focal cortical dysplasia to test whether reduced GluR2 expression in synapses of neocortical pyramidal neurons renders them susceptible to aberrant and potentially epileptogenic modulation by PKC and BDNF. In addition, using laser scanning photostimulation he will determine whether altered GluR2 expression and rewiring contribute to generation of neocortical epileptic discharge in this model. In project 3, Paul Buckmaster will use pilocarpine model of temporal lobe epilepsy and array electrodes to identify regions in the limbic system with the most predictive power for seizures, and then develop algorithms for seizure detection and prediction. He will also test whether altered connectivity between granule cells and interneurons explains a lack interneuronal recruitment in the preictal period. A core component will provide key administrative, histological and technical support for all projects. Together, the results of these studies will provide information regarding common vs distinct mechanisms of epileptogenesis in models of focal cortical, temporal lobe and post-traumatic epilepsies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS012151-36
Application #
8098036
Study Section
Special Emphasis Panel (ZNS1-SRB-G (10))
Program Officer
Fureman, Brandy E
Project Start
1997-12-01
Project End
2012-11-30
Budget Start
2011-07-01
Budget End
2012-11-30
Support Year
36
Fiscal Year
2011
Total Cost
$1,057,855
Indirect Cost
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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
Tani, Hiroaki; Dulla, Chris G; Farzampour, Zoya et al. (2014) A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron 81:888-900
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
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
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

Showing the most recent 10 out of 35 publications