A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy

Jehuda P. Sepkuty, Akiva S. Cohen, Christine Eccles, Azhar Rafiq, Kevin Behar, Raquelli Ganel, Douglas A. Coulter, Jeffrey D Rothstein

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6372-6379
Number of pages8
JournalJournal of Neuroscience
Volume22
Issue number15
StatePublished - Aug 1 2002

Fingerprint

Amino Acid Transport System X-AG
Excitatory Amino Acids
gamma-Aminobutyric Acid
Neurotransmitter Agents
Epilepsy
Glutamic Acid
Pyramidal Cells
Carisoprodol
Dendrites
Freezing
Seizures
Neurons

Keywords

  • Antisense
  • EAAC1
  • Epilepsy
  • GABA
  • Metabolism
  • Transport

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sepkuty, J. P., Cohen, A. S., Eccles, C., Rafiq, A., Behar, K., Ganel, R., ... Rothstein, J. D. (2002). A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. Journal of Neuroscience, 22(15), 6372-6379.

A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. / Sepkuty, Jehuda P.; Cohen, Akiva S.; Eccles, Christine; Rafiq, Azhar; Behar, Kevin; Ganel, Raquelli; Coulter, Douglas A.; Rothstein, Jeffrey D.

In: Journal of Neuroscience, Vol. 22, No. 15, 01.08.2002, p. 6372-6379.

Research output: Contribution to journalArticle

Sepkuty, JP, Cohen, AS, Eccles, C, Rafiq, A, Behar, K, Ganel, R, Coulter, DA & Rothstein, JD 2002, 'A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy', Journal of Neuroscience, vol. 22, no. 15, pp. 6372-6379.
Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K, Ganel R et al. A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. Journal of Neuroscience. 2002 Aug 1;22(15):6372-6379.
Sepkuty, Jehuda P. ; Cohen, Akiva S. ; Eccles, Christine ; Rafiq, Azhar ; Behar, Kevin ; Ganel, Raquelli ; Coulter, Douglas A. ; Rothstein, Jeffrey D. / A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy. In: Journal of Neuroscience. 2002 ; Vol. 22, No. 15. pp. 6372-6379.
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