Increased [³H]D-aspartate release and changes in glutamate receptor expression in the hippocampus of the mnd mouse

J Neurosci Res. 2012 Jun;90(6):1148-58. doi: 10.1002/jnr.22831. Epub 2012 Feb 3.

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a group of hereditary childhood diseases characterized mainly by lipopigment accumulation and a multisystemic pattern of symptoms including mental retardation, seizures, motor impairment, and blindness. The mnd mouse, carrying a mutation in the Cln8 gene, has been proposed as a model of epilepsy with mental retardation (EPMR, ornorthern epilepsy). We recently showed neuronal hyperexcitability and seizure hypersusceptibility in mnd mice. To elucidate the cellular mechanisms related to hippocampal hyperexcitability, the glutamatergic transmission and the expression of postsynaptic glutamate receptors were investigated in hippocampus. A significant increase in either spontaneous or KCl-stimulated overflow of [³H]D-aspartate was found in mnd mice compared with controls. This increase was maintained after DL-threo-β-benzyloxyaspartic acid (TBOA) treatment, suggesting a nonrelevant role for transporter-mediated release and supporting the involvement of exocytotic [³H]D-aspartate release. Accordingly, Ca²⁺-dependent overflow induced by ionomycin was also increased in mnd mice. Levels of glutamate 1-3 AMPA receptor subunits were increased, and levels of the NR2A NMDA receptor subunit were decreased in the hippocampus of mnd mice, suggesting an adaptive response to glutamate overstimulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Aspartic Acid / pharmacology
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Calcium Ionophores / pharmacology
  • D-Aspartic Acid / metabolism*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics*
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Ionomycin / pharmacology
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Potassium Chloride / pharmacology
  • Receptors, Glutamate / classification
  • Receptors, Glutamate / genetics
  • Receptors, Glutamate / metabolism*
  • Synaptosomes / metabolism
  • Tritium / metabolism

Substances

  • Calcium Ionophores
  • Cln8 protein, mouse
  • Glial Fibrillary Acidic Protein
  • Membrane Proteins
  • Receptors, Glutamate
  • benzyloxyaspartate
  • Tritium
  • Aspartic Acid
  • D-Aspartic Acid
  • Ionomycin
  • Potassium Chloride