(revised abstract) Excitotoxicity plays a central role in the pathophysiology of epilepsy, stroke and head trauma. Overactivation of glutamate receptors leads to calcium overloading, triggering neuronal cell death. However, efforts to develop ionotropic glutamate receptor antagonists as neuroprotective agents have yet to be successful;alternative molecular targets for developing neuroprotective compounds need to be identified. Metabotropic glutamate receptors (mGluRs) are a family of G-protein coupled glutamate receptors. Group I mGluRs (mGluR1 and mGluR5) have been implicated in seizures and excitotoxicity. However, the underlying mechanism of excitotoxicity mediated by group I mGluRs is not known. The main hypothesis of this application is that group I mGluRs contribute to seizure and excitotoxicity by activating the canonical transient receptor potential (TRPC) channels, which is a subgroup of the TRP superfamily of non-selective cation channels. TRPC channels are identified as store-operated calcium channels (SOC) and are also activated by G-protein coupled receptors coupled to phospholipase C, such as group I mGluRs. Our preliminary data suggest that the TRPC1/4/5 subgroup of TRPCs, activated by group I mGluRs, play a critical role in the plateau potential underlying the epileptiform burst firing induced by group I mGluR agonists in the lateral septum, a limbic structure highly vulnerable to seizure-induced excitotoxicity. To follow up on this initial finding, Specific Aim 1 of this study will examine whether this plateau potential can be abolished by eliminating TRPC channels with TRPC channel blockers and by using a genetic knockout approach for specific TRPC channels.
Specific Aim 1 will also determine whether there is a causal link between the mGluR-mediated plateau potential and acute excitotoxicity in the lateral septum. To determine whether TRPC channels contribute to seizure and excitotoxicity in vivo, the well-established pilocarpine- induced limbic seizure model will be used.
Specific Aim 2 will test the hypothesis that TRPC1 and TRPC4 contribute to susceptibility to pilocarpine-induced seizures in vivo;
and Specific Aim 3 will determine the distinct roles of TRPC1 and TRPC4 in neurodegeneration caused by pilocarpine-induced seizures in vivo. The long-term goal of this project is to elucidate the specific role of distinct TRPC family members in excitotoxicity. (description of abstract revision) The changes made to the abstract involve a deletion of all mention of experiments dealing with the use of the TRPC5(-/-) or TRPC1(-/-)/TRPC5(-/-) knockout mice. In addition, the signaling studies mentioned in the abstract have been deleted. All else has remained the same since the proposed experiments to remain in the grant address the original scope of the grant.

Public Health Relevance

section---no changes in this revision) The neuronal cell death caused by over exposure to a neurotransmitter called glutamate is a shared event in several neurological diseases, such as epilepsy, stroke and head trauma. New and effective treatment options for these neurological diseases are needed. Detailed knowledge on the mechanism of glutamate-induced neuronal cell death will help to identify new molecular target for drug development. A set of newly discovered ion channels called the canonical transient receptor potential (TRPC) channels may contribute to glutamate induced cell death because they can be activated by a glutamate receptor called metabotropic glutamate receptors. By using both in vitro and in vivo models of epilepsy, this study will determine whether these TRPC channels contribute to the generation of seizure and seizure-induced neuronal cell death. Results from this study will aid future drug development that will provide new treatment options for many neurological diseases. There are no changes in any of the following: Human embryonic stem cell check box Human subject coding Phase 3 clinical trial code

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS058503-01A2
Application #
7741176
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
2009-07-16
Project End
2011-06-30
Budget Start
2009-07-16
Budget End
2010-06-30
Support Year
1
Fiscal Year
2009
Total Cost
$345,782
Indirect Cost
Name
University of Arkansas for Medical Sciences
Department
Pharmacology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Phelan, Kevin D; Shwe, U Thaung; Cozart, Michael A et al. (2017) TRPC3 channels play a critical role in the theta component of pilocarpine-induced status epilepticus in mice. Epilepsia 58:247-254
Phelan, Kevin D; Shwe, U T; Williams, David K et al. (2015) Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale. Epilepsy Res 117:90-6
Phelan, Kevin D; Shwe, U Thaung; Abramowitz, Joel et al. (2014) Critical role of canonical transient receptor potential channel 7 in initiation of seizures. Proc Natl Acad Sci U S A 111:11533-8
Phelan, Kevin D; Shwe, U Thaung; Abramowitz, Joel et al. (2013) Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol Pharmacol 83:429-38
Phelan, Kevin D; Mock, Matthew M; Kretz, Oliver et al. (2012) Heteromeric canonical transient receptor potential 1 and 4 channels play a critical role in epileptiform burst firing and seizure-induced neurodegeneration. Mol Pharmacol 81:384-92