Neurotransmitter Supply and Demand in Epilepsy.

Abstract

Block of Glutamate-Glutamine Cycle Between Astrocytes and Neurons Inhibits Epileptiform Activity in Hippocampus Bacci A, Sancini G, Verderio C, Armano C, Pravettoni E, Fesce R, Franceschetti S, Matteoli M J Neurophysiol 2002;88:2302–2310 Recurrent epileptiform activity occurs spontaneously in cultured CNS neurons and in brain slices in which γ-aminobutyric acid (GABA) inhibition has been blocked. We demonstrate here that pharmacologic treatments, resulting in either the block of glutamine production by astrocytes or the inhibition of glutamine uptake by neurons, suppress or markedly decrease the frequency of spontaneous epileptiform discharges both in primary hippocampal cultures and in disinhibited hippocampal slices. These data point to an important role for the neuron-astrocyte metabolic interaction in sustaining episodes of intense rhythmic activity in the CNS, and thereby reveal a new potential target for antiepileptic treatments. A Neuronal Glutamate Transporter Contributes to Neurotransmitter GABA Synthesis and Epilepsy Sepkuty JP, Cohen AS, Eccles C, Rafiq A, Behar K, Ganel R, Coulter DA, Rothstein JD J Neuroscience 2002;22:6372–6379. The predominant neuronal glutamate transporter, EAAC1 (excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. Rare presynaptic localization is restricted to γ-aminobutyric acid (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 inhibitory postsynaptic potentials (mIPSCs) conducted in CA1 pyramidal neurons in slices from EAAC1 antisense-treated animals demonstrated a significant decrease in mIPSC amplitude, indicating decreased tonic inhibition. A 50% loss of hippocampal GABA levels was 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