A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy.
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.
Sepkuty
Jehuda P
JP
Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287-7247, USA.
Cohen
Akiva S
AS
Eccles
Christine
C
Rafiq
Azhar
A
Behar
Kevin
K
Ganel
Raquelli
R
Coulter
Douglas A
DA
Rothstein
Jeffrey D
JD
D000200:Action Potentials / Q000187:drug effects; D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D018728:Entorhinal Cortex / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters; D013788:Thalamus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology; D014741:Video Recording; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; D050491:Glutamate Plasma Membrane Transport Proteins; D016376:Oligonucleotides, Antisense; C493398:Slc1a1 protein, rat; D027981:Symporters; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid