Increased Expression of Endogenous GTRAP3-18 Causes Epilepsy, Possibly through Its Inhibitory Effect on EAAC1 Mediated Glutamate Transport.
Abstract number :
1.013
Submission category :
Year :
2001
Submission ID :
1676
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
J.P. Sepkuty, M.D., Neurology, Johns Hopkins University & hospital, Baltimore, MD; I. Orlov, Ph.D., Neurology, Johns Hopkins University, Baltimore, MD; A.M. Ruggiero, Graduate student, Neuroscience, Johns Hopkins University, Baltimore, MD; J.D. Rothstein,
RATIONALE: Reduced expression of the neuronal glutamate transporter EAAC1 leads to epileptic seizures (Soc. Neuro. Abs .618.3,1996; 584.7,1997; 150.3,2000; Epilepsia vol. 41 (suppl. 7):244, 2000- I.05). GTRAP3-18 is an endogenous negative modulator of EAAC1. Increasing the expression of GTRAP3-18 in cells reduces EAAC1-mediated glutamate transport activity. The expression of GTRAP3-18 can be up regulated by retinoic acid, which results in specific reduction of EAAC1-mediated glutamate transport. Because retinoic acid has been shown to increase the expression of GTRAP3-18 and reduce EAAC1-mediated glutamate transport, and because EAAC1 reduced expression and transport causes seizures, we hypothesized that intraventricular (ivt) administration of retinoic acid is epileptogenic.
METHODS: Male Sprague-Dawley rats (250-350g) were anesthetized with chloral hydrate 4%(1ml/100gr). Retinoic acid was administred intraventricularly by miniosmotic pumps in concentrations of 1, 2.5 and 5 micromolar. Rats were observed hourly for clinical seizure activity. (EEG and video recording is currently done- pending at the time of the abstract writing).
RESULTS: After 3-4 days of ivt retinoic acid (1-5 micromolar) treatment the rats developed epileptic seizures, the clinical severity of which increased in a dose dependent manner. Higher concentrations of retinoic acid (5 micromolar) produced early onset, severe seizures. Other direct methods of GTRAp3-18 delivery (e.g herpes viral vector, transgene over-expression) are also being explored.
CONCLUSIONS: These studies suggest that limbic hyperexcitability and epilepsy induced by decreased EAAC1 mediated glutamate transport, may be manipulated through GTRAP3-18. Regulation of glutamate uptake by GTRAP3-18 modulation of EAAC1 provides new possibilities for therapeutic interventions in epilepsy.
Support: NIH 33958