The central nervous system cannabinoid receptor (CB1) is one of the most abundant G-Protein coupled receptors in brain and mediates many of the effects of cannabinoid substances on neuronal function. Our laboratory has demonstrated that one hour of prolonged seizures (status epilepticus, SE) in the pilocarpine model of SE produces a long-term reorganization in the expression of the CB1 receptor ahd that these changes in CB1 expression persist for essentially the life of the animal. SE is a major neurological emergency that has a high mortality and morbidity, including acquired epilepsy (AE) and memory deficits. Our preliminary results suggest that the SE induced persistent changes in expression and function of the CB1 receptor are reorganized to be decreased on inhibitory and increased on excitatory nerve terminals, indicating that this long-term plasticity change may represent a significant modulator of neuronal function. This research effort will test the Central Hypothesis that SE (acute event) causes long lasting reorganization in the expression of the CB1 that results in persistent changes in the overall function of the endocannabinoid system, causing a greater inhibition of glutamate release and a smaller inhibition of GABA release in epileptic compared to control brain and ultimately in changes in the behavior of the animal, as manifested by memory deficits. To test this hypothesis we will conduct the following specific aims:
Aim 1. Evaluate whether SE alone or with the development of AE causes persistent rearrangements in the immunoreactivity and expression of the CB1 receptor in brain and evaluate the time course of these changes;
Aim 2. Determine if the SE induced changes in CB1 receptor expression are associated with corresponding changes in CB1 function as determined by G-protein activation, receptor binding and regulation of neurotransmiter release;
Aim 3. Determine the association of SE induced CB1 receptor reorganization on excitatory and inhibitory nerve terminals;
Aim 4. Determine the effects of long-term plasticity changes in CB1 expression and function on the long-term memory effects observed after SE. The goal of this research is to determine if changes in the expression of the CB1 system following SE contribute to altered neuronal excitability and memory deficits produced by SE. These studies may lead to the development of novel therapeutic interventions to reverse the effects of SE on AE and memory loss by pharmacologically regulating the endogenous CB1system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052529-04
Application #
7994399
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Whittemore, Vicky R
Project Start
2007-01-24
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2011-11-30
Support Year
4
Fiscal Year
2010
Total Cost
$322,679
Indirect Cost
Name
Virginia Commonwealth University
Department
Neurology
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Deshpande, Laxmikant S; Blair, Robert E; Phillips, Kristin F et al. (2016) Role of the calcium plateau in neuronal injury and behavioral morbidities following organophosphate intoxication. Ann N Y Acad Sci 1374:176-83
Sayers, Katherine W; Nguyen, Peter T; Blair, Robert E et al. (2012) Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain. Epilepsia 53:897-907
Ziobro, Julie M; Deshpande, Laxmikant S; Delorenzo, Robert J (2011) An organotypic hippocampal slice culture model of excitotoxic injury induced spontaneous recurrent epileptiform discharges. Brain Res 1371:110-20
Deshpande, Laxmikant S; Blair, Robert E; DeLorenzo, Robert J (2011) Prolonged cannabinoid exposure alters GABA(A) receptor mediated synaptic function in cultured hippocampal neurons. Exp Neurol 229:264-73
Deshpande, Laxmikant S; DeLorenzo, Robert J (2011) Acetaminophen inhibits status epilepticus in cultured hippocampal neurons. Neuroreport 22:15-8
Carter, Dawn S; Deshpande, Laxmikant S; Rafiq, Azhar et al. (2011) Characterization of spontaneous recurrent epileptiform discharges in hippocampal-entorhinal cortical slices prepared from chronic epileptic animals. Seizure 20:218-24
Deshpande, Laxmikant S; Carter, Dawn S; Blair, Robert E et al. (2010) Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate. Toxicol Sci 116:623-31
Nagarkatti, Nisha; Deshpande, Laxmikant S; Carter, Dawn S et al. (2010) Dantrolene inhibits the calcium plateau and prevents the development of spontaneous recurrent epileptiform discharges following in vitro status epilepticus. Eur J Neurosci 32:80-8
Falenski, Katherine W; Carter, Dawn S; Harrison, Anne J et al. (2009) Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus. Brain Res 1262:64-72
Nagarkatti, Nisha; Deshpande, Laxmikant S; DeLorenzo, Robert J (2009) Development of the calcium plateau following status epilepticus: role of calcium in epileptogenesis. Expert Rev Neurother 9:813-24

Showing the most recent 10 out of 26 publications