Acute seizures develop in up to 80 pecent of cases of moderate to severe head trauma, indicating serious cortical damage. The majority of these individuals will have chronic seizures (epilepsy). Concepts regarding the mechanisms underlying epileptogenesis and cell damage have focused on excitotoxicity. Excitotoxicity consists of a cascade of events triggered by excitatory amino acid transmitters, calcium influx via transmitter-gated and voltage-dependent channels, and intracellular calcium release, which then activate autodestructive processes ending in membrane damage and cell death. Epileptogenesis, signaling the dominance of excitation over inhibition can occur at any stage in the excitotoxic process. Such inhibitory failure following trauma cona only be understood by studying local neuronal circuits. A model of traumatic neocortical injury has been developed in order to investigate the mechanisms of excitotoxicity and epileptogenesis. This model utilizes rat in vitro somatosensory cortical slices, wherein after removal of the superficial third of coronal slices, over half the isolated deep segments express epileptiform activity. Preliminary findings postulate that hyperexcitability results from GABAergic disinhibition owing to physical removal of superficial inhibitory circuits and glutamate-triggered increases in intracellular calcium. Experiments will be performed in order to test this hypotheses with regarded to these issues: 1) Strength of glutamatergic excitation and fast GABAergic inhibition in deep neurons from intact versus damaged preparations, 2) Properties of monosynaptic fast GABAergic inhibition in intact versus damage preparations, 3) Intracellular calcium concentration in pyramidal cells after damage, 4) Whether increased intracellular calcium concentration leads to fast GABAergic disinhibition in deep pyramidal neurons, and 5) Testing whether lowering the intracellular calcium concentration in damaged preparations restores fat inhibition. Experiments will utilize standard intracellular or patch clamp recordings of deep pyramidal cells and videoimaging of calcium-sensitive dyes to allow correlation of inhibitory strength with intracellular calcium concentration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038132-02
Application #
6188186
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
2
Fiscal Year
2000
Total Cost
$178,601
Indirect Cost
Name
Suny Downstate Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Brooklyn
State
NY
Country
United States
Zip Code
11203