Epilepsy results from abnormal recruitment of recurrent excitatory synaptic circuits in the neocortex. The long term goals of this project are to determine the mechanisms underlying epileptic recruitment and to develop therapies that will prevent it. In the developing brain excitatory neocortical networks are synaptically connected via an immature form of postsynaptic ionotropic glutamate receptor that lack the GluR2 receptor subunit. Synapses lacking this subunit show dynamic forms of synaptic plasticity not normally seen in mature neurons, which prominently express synaptic GluR2 receptors. Our preliminary data suggests that in the cortical freeze lesion (microgyrus) model of focal cortical dysplasia, neocortical pyramidal neurons express immature forms of synaptic glutamate receptors and display prominent epileptiform hyperexcitability that is recruited by focal molecular uncaging of glutamate. In the first aim of the proposed experiments we will use in vitro electrophysiological means to determine the mechanisms underlying BDNF- and PKC- mediated plasticity of synaptic receptors in immature neocortical circuits. In addition we will test whether such plasticity exists in synapses of the microgyrus model. In the second aim we will utilize laser scanning photostimulation to determine the mechanisms underlying the abnormal recruitment of epileptiform electrical responses in the microgyrus model. The results of these studies will provide information relevant to our understanding of the mechanisms underlying focal cortical seizures, and may indicate therapeutic targets for antiepileptic drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS012151-35
Application #
8098033
Study Section
Special Emphasis Panel (ZNS1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
35
Fiscal Year
2010
Total Cost
$294,104
Indirect Cost
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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