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The Journal of Neuroscience, August 1, 2002, 22(15):6372-6379
A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy
Jehuda P. Sepkuty1, Akiva S. Cohen2, Christine Eccles1, Azhar Rafiq3, Kevin Behar4, Raquelli Ganel1, Douglas A. Coulter2, and Jeffrey D. Rothstein1 1 Departments of Neurology and Neuroscience, Johns Hopkins University, Baltimore, Maryland 21287, 2 Departments of Pediatrics and Neuroscience, University of Pennsylvania School of Medicine and the Stokes Research Institute of Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, 3 Medical College of Virginia of Virginia Commonwealth University, Richmond, Virginia 23284, and 4 Department of Psychiatry, Yale University, New Haven, Connecticut 06520
The predominant neuronal glutamate transporter, EAAC1 (for excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to GABA terminals. Because glutamate is a precursor for GABA synthesis, we hypothesized that EAAC1 may play a role in regulating GABA synthesis and, thus, could cause epilepsy in rats when inactivated. Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring-freezing episodes and electrographic (EEG) seizures. Extracellular hippocampal and thalamocortical slice recordings showed excessive excitability in antisense-treated rats. Patch-clamp recordings of miniature IPSCs (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. There was a 50% loss of hippocampal GABA levels associated with knockdown of EAAC1, and newly synthesized GABA from extracellular glutamate was significantly impaired by reduction of EAAC1 expression. EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism.
Key words: EAAC1; transport; antisense; GABA; metabolism; epilepsy
Copyright © 2002 Society for Neuroscience 0270-6474/02/22156372-08$05.00/0
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