Collapse of extracellular glutamate regulation during epileptogenesis: down‐regulation and functional failure of glutamate transporter function in rats with chronic seizures induced by kainic acid

Abstract

We used northern and western blotting to measure the quantity of glutamate and GABA transporters mRNA and their proteins within the hippocampal tissue of rats with epileptogenesis. Chronic seizures were induced by amygdalar injection of kainic acid 60 days before death. We found that expression of the mRNA and protein of the glial glutamate transporters GLAST and GLT-1 were down-regulated in the kainic acid-administered group. In contrast, EAAC-1 and GAT-3 mRNA and their proteins were increased, while GAT-1 mRNA and protein were not changed. We performed in vivo microdialysis in the freely moving state. During the interictal state, the extracellular glutamate concentration was increased, whereas the GABA level was decreased in the kainic acid group. Following potassium-induced depolarization, glutamate over¯ow was higher and the recovery time to the basal release was prolonged in the kainic acid group relative to controls. Our data suggest that epileptogenesis in rats with kainic acid-induced chronic seizures is associated with the collapse of extracellular glutamate regulation caused by both molecular down-regulation and functional failure of glutamate transport.

Guanosine and its role in neuropathologies

“…Since glutamate is the main excitatory neurotransmitter in the brain, its participation in many aspects of the initiation and propagation of seizures is well established and a role for astrocytic glutamate transporters in the neuropathology of this disorder has been proposed [60,[110][111][112]. In fact, the importance of astrocytic uptake can be emphasized by the observation that knock-out mice for specific types of astrocytic glutamate transporters exhibit lethal spontaneous seizures [111,113].…”

Elevated basal glutamate and unchanged glutamine and GABA in refractory epilepsy: Microdialysis study of 79 patients at the yale epilepsy surgery program

“…Glutamate levels were also elevated in patients with nonlocalizable seizures, with some of the highest levels found in in the developmental and acquired cortical lesions. The possible causes of such glutamate accumulation are diverse, including metabolic and energetic failure, transporter impairment, neuronal and glial release, increased blood-brain barrier permeability, or impaired clearance of the massive glutamate release associated with seizures 3,[15][16][17] and may depend on the pathophysiology underlying the etiology of the disease. In turn, the elevated basal glutamate may also promote seizure propagation through complex glial-neuronal signaling, and the FIGURE 5: Basal extracellular glutamine in the cortex and hippocampus.…”

Hypersensitive Glutamate Signaling Correlates with the Development of Late-Onset Behavioral Morbidity in Diffuse Brain-Injured Circuitry

“…In contrast, glutamate transporter protein expression was downregulated by 20-50% in contused or peri-contusional tissue from humans and rodents up to 72 h post-injury (Rao et al, 1998;van Landeghem et al, 2001van Landeghem et al, ,2006Yi and Hazell, 2006), indicating a role for glutamate dysregulation in necrotic contusion formation. Similarly, KCl-evoked glutamate overflow (microdialysis) was elevated in an established kainic acid-induced epilepsy model as a result of downregulated glutamate transporters (GLT-1 and GLAST; Ueda et al, 2001). Thus, in diffuse brain injury without contusion, glutamate transporter gene expression and function may not substantially contribute to the late-onset increase seen in tonic and evoked glutamate concentrations.…”