Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy

TY - JOUR

T1 - Gene expression of glutamate metabolizing enzymes in the hippocampal formation in human temporal lobe epilepsy

AU - Eid, Tore

AU - Lee, Tih-Shih W

AU - Wang, Yue

AU - Perez, Edgar

AU - Peréz, Edgar

AU - Drummond, Jana

AU - Lauritzen, Fredrik

AU - Bergersen, Linda H

AU - Meador-Woodruff, James H

AU - Spencer, Dennis D

AU - de Lanerolle, Nihal C

AU - McCullumsmith, Robert E

N1 - Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

PY - 2013/2

Y1 - 2013/2

N2 - PURPOSE: Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE). Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear. A better understanding of the regulatory mechanisms of GS and PAG could facilitate the discovery of novel therapeutics for TLE.METHODS: We used in situ hybridization on histologic sections to assess the distribution and quantity of messenger RNA (mRNA) for GS and PAG in subfields of hippocampal formations from the following: (1) patients with TLE and concomitant hippocampal sclerosis, (2) patients with TLE and no hippocampal sclerosis, and (3) nonepilepsy autopsy subjects.KEY FINDINGS: GS mRNA was increased by ~50% in the CA3 in TLE patients without hippocampal sclerosis versus in TLE patients with sclerosis and in nonepilepsy subjects. PAG mRNA was increased by >100% in the subiculum in both TLE patient categories versus in nonepilepsy subjects. PAG mRNA was also increased in the CA1, CA2, CA3, and dentate hilus in TLE without hippocampal sclerosis versus in TLE with sclerosis. Finally, PAG mRNA was increased in the dentate gyrus in TLE with sclerosis versus in nonepilepsy subjects, and also increased in the hilus in TLE without sclerosis versus in TLE with sclerosis.SIGNIFICANCE: These findings demonstrate complex changes in the expression of mRNAs for GS and PAG in the hippocampal formation in TLE, and raise the possibility that both transcriptional and posttranscriptional mechanisms may underlie the regulation of GS and PAG proteins in the epileptic brain.

AB - PURPOSE: Increased interictal concentrations of extracellular hippocampal glutamate have been implicated in the pathophysiology of temporal lobe epilepsy (TLE). Recent studies suggest that perturbations of the glutamate metabolizing enzymes glutamine synthetase (GS) and phosphate activated glutaminase (PAG) may underlie the glutamate excess in TLE. However, the molecular mechanism of the enzyme perturbations remains unclear. A better understanding of the regulatory mechanisms of GS and PAG could facilitate the discovery of novel therapeutics for TLE.METHODS: We used in situ hybridization on histologic sections to assess the distribution and quantity of messenger RNA (mRNA) for GS and PAG in subfields of hippocampal formations from the following: (1) patients with TLE and concomitant hippocampal sclerosis, (2) patients with TLE and no hippocampal sclerosis, and (3) nonepilepsy autopsy subjects.KEY FINDINGS: GS mRNA was increased by ~50% in the CA3 in TLE patients without hippocampal sclerosis versus in TLE patients with sclerosis and in nonepilepsy subjects. PAG mRNA was increased by >100% in the subiculum in both TLE patient categories versus in nonepilepsy subjects. PAG mRNA was also increased in the CA1, CA2, CA3, and dentate hilus in TLE without hippocampal sclerosis versus in TLE with sclerosis. Finally, PAG mRNA was increased in the dentate gyrus in TLE with sclerosis versus in nonepilepsy subjects, and also increased in the hilus in TLE without sclerosis versus in TLE with sclerosis.SIGNIFICANCE: These findings demonstrate complex changes in the expression of mRNAs for GS and PAG in the hippocampal formation in TLE, and raise the possibility that both transcriptional and posttranscriptional mechanisms may underlie the regulation of GS and PAG proteins in the epileptic brain.

KW - Adolescent

KW - Adult

KW - Autopsy

KW - Child

KW - Electroencephalography

KW - Epilepsy, Temporal Lobe/enzymology

KW - Female

KW - Gene Expression Regulation, Enzymologic/genetics

KW - Glutamate-Ammonia Ligase/metabolism

KW - Glutamic Acid/metabolism

KW - Glutaminase/metabolism

KW - Hippocampus/enzymology

KW - Humans

KW - In Situ Hybridization

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - RNA, Messenger/biosynthesis

KW - Young Adult

U2 - 10.1111/epi.12008

DO - 10.1111/epi.12008

M3 - Journal article

C2 - 23384343

SN - 0013-9580

VL - 54

SP - 228

EP - 238

JO - Epilepsia

JF - Epilepsia

IS - 2

ER -