Increased [³H]D-aspartate release and changes in glutamate receptor expression in the hippocampus of the mnd mouse.
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.
Department of Biochemistry and Molecular Pharmacology, Mario Negri Institute for Pharmacological Research, Milano, Italy. bigini@marionegri.it
Paolo
P
Bigini
Marco
M
Milanese
Fabrizio
F
Gardoni
Annalisa
A
Longhi
Tiziana
T
Bonifacino
Sara
S
Barbera
Elena
E
Fumagalli
Monica
M
Di Luca
Tiziana
T
Mennini
Giambattista
G
Bonanno
D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D026603:D-Aspartic Acid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011189:Potassium Chloride / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
D061207:Calcium Ionophores; C498493:Cln8 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D017470:Receptors, Glutamate; C120673:benzyloxyaspartate; D014316:Tritium; D001224:Aspartic Acid; D026603:D-Aspartic Acid; D015759:Ionomycin; D011189:Potassium Chloride