TY - JOUR
T1 - Genetic deletion of the neuronal glutamate transporter, EAAC1, results in decreased neuronal death after pilocarpine-induced status epilepticus
AU - Lane, Meredith C.
AU - Jackson, Joshua G.
AU - Krizman, Elizabeth N.
AU - Rothstein, Jeffery D.
AU - Porter, Brenda E.
AU - Robinson, Michael B.
N1 - Funding Information:
This research was supported by an NIH grant R01 HD060132 . This work was also supported by the Neuroscience Core of the Institutional Intellectual and Developmental Disabilities Research Center ( P30 HD26979 ). J.G.J. was partially supported by T32NS007413.
PY - 2014/7
Y1 - 2014/7
N2 - 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 h 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.
AB - 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 h 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.
KW - Cell death
KW - EAAC1
KW - EAAT3
KW - Glutamate transport
KW - Pilocarpine
KW - Seizure
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U2 - 10.1016/j.neuint.2013.11.013
DO - 10.1016/j.neuint.2013.11.013
M3 - Article
C2 - 24334055
AN - SCOPUS:84902544685
SN - 0197-0186
VL - 73
SP - 152
EP - 158
JO - Neurochemistry International
JF - Neurochemistry International
IS - 1
ER -