A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy

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.

The Transcription Factor Regulatory Factor X1 Increases the Expression of Neuronal Glutamate Transporter Type 3

“…EAAT3, in hippocampal slices decreased the inhibitory neurotransmitter ␥-aminobutyric acid (GABA)-mediated inhibitory postsynaptic current and miniature inhibitory postsynaptic current due to a reduction of GABA synthesis because glutamate uptaken by neuronal EAATs is a substrate for GABA synthesis (22). These results are consistent with the data from an early study showing that antisense knockdown of EAAT3 induced epilepsy in rats and that the hippocampal slices from these rats had a decrease in GABA synthesis, total GABA levels, and miniature inhibitory postsynaptic current (23). Thus, EAAT3 plays a role in maintaining the balance of glutamate/GABA neurotransmission.…”

Glutamate Spillover Modulates GABAergic Synaptic Transmission in the Rat Midbrain Periaqueductal Grey via Metabotropic Glutamate Receptors and Endocannabinoid Signaling

“…This effect was likely to be produced via a presynaptic mechanism, because it was associated with an increase in the paired-pulse ratio evoked IPSCs and a reduction in the frequency but not the amplitude of spontaneous miniature IPSCs, as demonstrated previously for opioids and cannabinoids in the PAG (Vaughan and Christie, 1997;Vaughan et al, 2000). The lack of effect on miniature IPSC amplitude and kinetics also indicates that, under our experimental conditions, TBOA did not reduce GABAergic transmission via disruption of presynaptic glutamate transporter-mediated GABA synthesis, as has been demonstrated at other CNS synapses (Sepkuty et al, 2002;Mathews and Diamond, 2003).…”

Dynamic Regulation of Synaptic GABA Release by the Glutamate-Glutamine Cycle in Hippocampal Area CA1

“…Depleting or enhancing intraterminal cytoplasmic concentrations of neurotransmitter would therefore be expected to decrease or enhance vesicle content, respectively, as has been observed experimentally in various synapses (Murphy et al, 1998;Pothos et al, 1998), including hippocampal inhibitory synapses (Engel et al, 2001;Sepkuty et al, 2002;Mathews and Diamond, 2003). A recent study consistent with this idea demonstrated that GABA vesicle content is in dynamic equilibrium with intraterminal glutamate concentrations (Mathews and Diamond, 2003).…”