title: 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 24h 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.
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Meredith C
authors: MC
authors: Lane
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Joshua G
authors: JG
authors: Jackson
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Elizabeth N
authors: EN
authors: Krizman
authors: Department of Neurology and Neuroscience, Johns Hopkins University, Brain Sciences Institute, Baltimore, MD 21205, USA.
authors: Jeffery D
authors: JD
authors: Rothstein
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Brenda E
authors: BE
authors: Porter
authors: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pharmacology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: robinson@upenn.edu.
authors: Michael B
authors: MB
authors: Robinson
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003292:Convulsants; D050580:Excitatory Amino Acid Transporter 3 / Q000235:genetics*; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D010862:Pilocarpine; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*
chemical_list: D003292:Convulsants; D050580:Excitatory Amino Acid Transporter 3; C493399:Slc1a1 protein, mouse; D010862:Pilocarpine
keywords: Cell death; EAAC1; EAAT3; Glutamate transport; Pilocarpine; Seizure