Epilepsy is a major neurologic public health problem that affects an estimated 3 million Americans. Despite its prevalence and several decades of research efforts, our understanding about the cellular mechanisms underlying intractable epilepsy remains limited. Most of the epilepsy research has been focused on the electrophysiological consequences of acute seizures leading to the discovery of several anticonvulsants that are currently available. However, our limited understanding about the mechanisms underlying the chronic alterations of epilepsy has hampered the development of true """"""""anti-epileptic"""""""" drugs. It is now recognized that repeated seizures induced morphological alterations in the limbic structures of human temporal lobe epilepsy and in chronic animal models of this condition. These morphological alterations include sprouting of the mossy fiber pathway that forms new recurrent excitatory collaterals leading to a permanent hyperexcitability of the dentate gyrus. The proposed research investigates the exciting possibility that this putative cellular mechanism of epilepsy, sproutinginduced hyperexcitability, is a major contributor in another seizurevulnerable limbic structure, the CA1 region of the hippocampus. I have obtained anatomical evidence of sprouting in the CA1 region in 4 chronic models of epilepsy, thus, providing a rationale for the hypothesis described in this proposal. As the functional consequences of this newly recognized phenomenon in CA1 neurons are not known, I would like to extend my anatomical studies by using neurophysiological techniques to address this question. The hypothesis of this grant proposal extension has not changed and is that seizureinduced synaptic reorganization in the CA1 region is a mechanism that leads to hyperexcitability in this circuitry enhancing the susceptibility to further seizures. We have made progress in recording from CA1 pyramidal neurons, but we still need to determine whether there is a correlation between the anatomical distribution of Kainic acid induced hyperexcitability in the electrophysiological properties of CA1 pyramidal neurons and the anatomical distribution of Kainic acid induced synaptic reorganization in the CA1 region. During the first 18 months of the award, there was no Kainic acid available (worldwide shortage). We evaluated the Pilocarpine model, and we determined that although CA1 synaptic reorganization occurs, it was not robust enough for the proposed studies as compared to prior experiments with Kainic acid. As Kainic acid became available in May 2000, we began to examine the relationship between hyperexcitability and sprouting in the CA1 region of the hippocampus. In August 2000, I accepted a position in UTHSCSA, and I moved in October 2000. The proposed experiments will better define the mechanisms of chronic epileptogenesis in Temporal Lobe Epilepsy (TLE) and may lead to the development of novel pharmacological approaches for the treatment of TLE. For the Educational component of the MCSDA, I now attend the pharmacology seminars at UTHSCSA and have selected Dr. Steven Mifflin as my new mentor owing to his extensive experience in brain slice neurophysiology. I will devote at least 75% of effort to research, and the remaining effort for clinical care in Epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
2K08NS002078-05
Application #
6438879
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jacobs, Margaret
Project Start
1998-09-30
Project End
2004-02-14
Budget Start
2002-02-15
Budget End
2003-02-14
Support Year
5
Fiscal Year
2002
Total Cost
$142,669
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Verellen, Rebecca M; Cavazos, Jose E (2010) Post-traumatic epilepsy: an overview. Therapy 7:527-531
Cross, Devin J; Cavazos, Jose E (2007) Synaptic reorganization in subiculum and CA3 after early-life status epilepticus in the kainic acid rat model. Epilepsy Res 73:156-65
Cavazos, Jose E; Cross, Devin J (2006) The role of synaptic reorganization in mesial temporal lobe epilepsy. Epilepsy Behav 8:483-93
Cavazos, J E; Jones, S M; Cross, D J (2004) Sprouting and synaptic reorganization in the subiculum and CA1 region of the hippocampus in acute and chronic models of partial-onset epilepsy. Neuroscience 126:677-88
Cavazos, Jose E; Zhang, Peisu; Qazi, Romena et al. (2003) Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats. J Comp Neurol 458:272-92