Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus

Abstract

Excitatory amino acid carrier 1 (EAAC1, also called EAAT3) is a Na+-dependent glutamate transporter expressed by both glutamatergic and GABAergic neurons. It provides precursors for the syntheses of glutathione and GABA and contributes to the clearance of synaptically released glutamate. Mice deleted of EAAC1 are more susceptible to neurodegeneration in models of ischemia, Parkinson’s disease, and aging. Antisense knock-down of EAAC1 causes an absence seizure-like phenotype. Additionally, EAAC1 expression increases after chemonvulsant-induced seizures in rodent models and in tissue specimens from patients with refractory epilepsy. The goal of the present study was to determine if the absence of EAAC1 affects the sensitivity of mice to seizure-induced cell death. A chemoconvulsant dose of pilocarpine was administered to EAAC1−/− mice and to wild-type controls. Although EAAC1−/− mice experienced increased latency to seizure onset, no significant differences in behavioral seizure severity or mortality were observed. We examined EAAC1 immunofluorescence 24 hours after pilocarpine administration and confirmed that pilocarpine causes an increase in EAAC1 protein. Forty-eight hours after induction of seizures, cell death was measured in hippocampus and in cortex using Fluoro-Jade C. Surprisingly, there was ~2-fold more cell death in area CA1 of wild-type mice than in the corresponding regions of the EAAC1−/− mice. Together, these studies indicate that absence of EAAC1 results in either a decrease in pilocarpine-induced seizures that is not detectable by behavioral criteria (surprising, since EAAC1 provides glutamate for GABA synthesis), or that the absence of EAAC1 results in less pilocarpine/seizure-induced cell death, possible explanations as discussed.

The importance of the excitatory amino acid transporter 3 (EAAT3)

“…However, a recent study found reduced neuronal death in the CA1 region in pilocarpine-induced status epilepticus of EAAT3 KO mice (Lane et al, 2014). These data were interpreted to indicate that, under the experimental conditions used, EAAT3 reverses transport, since during a seizure ATP levels decline and the sodium driving force collapses (Streck et al, 2006; Kovac et al, 2012), leading to the protective effect of knocking out EAAT3 and implicating its role in seizure kindling.…”

Reduced Slc1a1 expression is associated with neuroinflammation and impaired sensorimotor gating and cognitive performance in mice: Implications for schizophrenia

“…Consistent with this idea, EAAT3-null mice present with decreased neuronal GSH levels, increased indicators of neuronal oxidative stress, age-dependent neurodegeneration as well as cognitive impairment and behavioral abnormalities [ 11 , 16 , 17 ]. These mice are also more susceptible to neurodegeneration in models of ischemia, Parkinson’s disease, and aging [ 8 , 11 , 18 , 19 , 20 , 21 ]. Interestingly, it has been observed that treatment of mice with N-acetylcysteine (NAC), a membrane-permeable cysteine precursor, attenuates or prevents the biochemical and behavioral abnormalities in EAAT3-null mice [ 11 , 17 , 19 , 22 ].…”

Dysfunction of EAAT3 Aggravates LPS-Induced Post-Operative Cognitive Dysfunction

“…EAAT3, encoded by the SLC1A1 gene, ubiquitously exists in the brain and is enriched in the neurons of hippocampus and cortex [ 6 , 7 ]. Previous studies have found out that EAAT3 dysfunction may lead to neuropsychiatric diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease, epilepsy, and schizophrenia [ 8 , 9 , 10 , 11 , 12 , 13 ]. Evidence has also shown that SLC1A1 /EAAT3 overexpression could cause pathologic effects on dopaminergic neurotransmission and increase the risk of obsessive-compulsive disorder (OCD) [ 14 , 15 ].…”