A principal goal of epilepsy research is to identify and develop novel treatment strategies for seizure control that may be relatively selective for modulation of the synaptically reorganized circuitry in the epileptic brain. The objective of this Exploratory/Developmental (R21) research proposal is to identify the effects of exogenous and endogenous cannabinoids on neurons of the dentate gyrus in mice with pilocarpine-induced temporal lobe epilepsy (TLE), characterized by chronic spontaneous seizures, mossy fiber sprouting, and increased neuronal excitability and synchrony. The use of cannabinoids for treating seizure disorders has been proposed, but results of case study analyses have been mixed. The goal of this proposal is to determine how cannabinoids modulate activity in the dentate gyrus in a murine model of TLE in order to understand effects of the substance on a system that has undergone synaptic reorganization (versus effects on normal neural circuits). Most known central effects of cannabinoids are mediated by cannabinoid type 1 receptors (CB1R), usually located on presynaptic terminals. In the hippocampus, cannabinoids suppress synaptic input-especially feedback inhibition--to principal neurons, including dentate gyrus granule cells. Although cannabinoids appear to suppress some types of seizures, the cellular """"""""disinhibitory"""""""" properties appear to be proconvulsive in normal brains. Recent analyses suggest that cannabinoids may suppress seizure activity in the epileptic brain. However, no studies at the cellular level have been performed in the dentate gyrus in an animal model of TLE (i.e., having cell loss, axon sprouting, and synaptic reorganization). Preliminary data presented here suggest that, in the absence of GABAA receptor-mediated inhibition, cannabinoids can inhibit epileptiform discharges that are attributable to activation of newly-formed recurrent excitatory circuitry in the dentate gyrus in mice with pilocarpine-induced TLE. Using electrophysiological, anatomical, and molecular biological techniques, the hypotheses that: 1) cannabinoids inhibit new recurrent excitatory circuitry; 2) cannabinoids inhibit granule cells directly, and 3) CB1R expression is upregulated in animals with TLE and synaptic reorganization will be tested in a murine model of TLE developed in this lab. Understanding these effects may promote more effective treatment strategies designed specifically for TLE patients, whose brains have undergone a degree of synaptic reorganization. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS052302-01
Application #
6958047
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jacobs, Margaret
Project Start
2005-07-01
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$171,703
Indirect Cost
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118