TY - JOUR
T1 - Increased [ 3H]D-aspartate release and changes in glutamate receptor expression in the hippocampus of the mnd mouse
AU - Bigini, Paolo
AU - Milanese, Marco
AU - Gardoni, Fabrizio
AU - Longhi, Annalisa
AU - Bonifacino, Tiziana
AU - Barbera, Sara
AU - Fumagalli, Elena
AU - Di Luca, Monica
AU - Mennini, Tiziana
AU - Bonanno, Giambattista
PY - 2012/6
Y1 - 2012/6
N2 - 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, Ca 2+-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.
AB - 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, Ca 2+-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.
KW - Epilepsy
KW - Excitotoxicity
KW - Glutamate release
KW - Mnd mice
KW - Neuronal ceroid lipofuscinoses
KW - Neuronal hyperexcitability
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U2 - 10.1002/jnr.22831
DO - 10.1002/jnr.22831
M3 - Article
C2 - 22302580
AN - SCOPUS:84859446256
VL - 90
SP - 1148
EP - 1158
JO - Journal of Neuroscience Research
JF - Journal of Neuroscience Research
SN - 0360-4012
IS - 6
ER -