One of the most common types of epilepsy - mesial temporal lobe epilepsy (MTLE) - is characterized by spontaneous and recurrent partial seizures. Furthermore, many patients with MTLE cannot control their seizures with current antiepileptic drugs. Novel approaches aimed at predicting and treating impending mesial temporal lobe seizures are therefore particularly important. Thus, the overall goal of the present proposal is to explore the mechanism of seizure generation in MTLE, thereby facilitating the discovery of candidate biomarkers of and more efficacious therapies for this disorder. Recent studies have suggested that a deficiency in glutamine synthetase in the hippocampus is implicated in the generation of seizures in MTLE (Eid et al. Lancet 2004;363: 28-37). Using state-of-the art methods in continuous video intracranial EEG monitoring, microdialysis, immunogold electron microscopy, 13C- and 15N-isotope labeling, and tandem mass spectrometry, the role of the glutamine synthetase deficiency in the generation of seizures will be systematically explored in a newly developed laboratory model of MTLE.
In Specific Aim 1, the relationship among hippocampal glutamine synthetase deficiency, intra- and extracellular glutamate concentrations, seizures, and hippocampal pathology will be assessed. The hypothesis is that a deficiency in glutamine synthetase leads to chronic high concentrations of glutamate in astrocytes and the extracellular space of the hippocampus with particularly high glutamate levels in individuals suffering from severe seizures and extensive brain damage.
In Specific Aim 2, transient elevations in naturally occurring brain chemicals will be explored as potential triggers of "spontaneous" seizures in MTLE. The hypothesis is that such triggers cause a transient surge in extracellular glutamate in the hippocampus with "spontaneous" seizures as the ultimate consequence. Finally, in Specific Aim 3, the concept that restoration of glutamine synthetase in the epileptogenic hippocampus may be used as a cure of MTLE will be evaluated. The hypothesis is that restoration of glutamine synthetase in the hippocampus leads to cessation of seizures even in the presence of extensive brain pathology.

Public Health Relevance

Many patients with epilepsy suffer from unpredictable attacks of debilitating seizures that cannot be treated with current antiepileptic drugs. New diagnostic tests and better treatments of epileptic seizures are therefore necessary. This proposal seeks to identify novel diagnostic markers and treatments of one of the most common forms of drug resistant epilepsies, mesial temporal lobe epilepsy (MTLE).

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070824-04
Application #
8464815
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Whittemore, Vicky R
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$342,373
Indirect Cost
$135,501
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Dhaher, Roni; Damisah, Eyiyemisi C; Wang, Helen et al. (2014) 5-aminovaleric acid suppresses the development of severe seizures in the methionine sulfoximine model of mesial temporal lobe epilepsy. Neurobiol Dis 67:18-23
Eid, Tore; Tu, Nathan; Lee, Tih-Shih W et al. (2013) Regulation of astrocyte glutamine synthetase in epilepsy. Neurochem Int 63:670-81
Eid, Tore; Lee, Tih-Shih W; Wang, Yue et al. (2013) Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy. Epilepsia 54:228-38
Lauritzen, Fredrik; Heuser, Kjell; de Lanerolle, Nihal C et al. (2012) Redistribution of monocarboxylate transporter 2 on the surface of astrocytes in the human epileptogenic hippocampus. Glia 60:1172-81
Lauritzen, Fredrik; Perez, Edgar L; Melillo, Eric R et al. (2012) Altered expression of brain monocarboxylate transporter 1 in models of temporal lobe epilepsy. Neurobiol Dis 45:165-76