Lack of PSD-95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway

被引:40
作者
Gardoni, F
Bellone, C
Viviani, B
Marinovich, M
Meli, E
Pellegrini-Giampietro, DE
Cattabeni, F
Di Luca, M
机构
[1] Univ Milan, Ctr Excellence Neurodegenerat Dis, I-20133 Milan, Italy
[2] Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy
[3] Univ Florence, Dept Preclin & Clin Pharmacol, I-50139 Florence, Italy
关键词
AMPA receptor; NMDA receptor complex; postsynaptic density; rat;
D O I
10.1046/j.1460-9568.2002.02141.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The PSD-95 protein family organizes the glutamatergic postsynaptic density and it is involved in the regulation of the excitatory signal at central nervous system synapses. We show here that PSD-95 deficiency by means of antisense oligonucleotides induces significant neuronal cell death within 24 h both in primary hippocampal cultures and in organotypic hippocampal slices. On the other hand, cultured cortical neurons are spared by PSD-95 antisense toxicity until they reach a NR2A detectable protein level (24 days in vitro). The neurotoxic event is characterized by increased alphaCaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of alphaCaMKII association, we found increased GluR1 delivery to cell surface in cultured hippocampal neurons paralleled by AMPA-dependent increase in [Na+ ](I) levels. In addition, both CaMKII specific inhibitor KN-93 and AMPA receptor antagonists CNQX and NBQX rescued neuronal survival to control values. On the other hand, both the NMDA channel blocker MK-801 and Dantrolene, an inhibitor of calcium release from ryanodine-sensitive endoplasmic reticulum stores, failed to have any effect on neuronal survival in PSD-95 deficient neurons. Thus, our data provide clues that PSD-95 reduced expression in neurons is responsible for neuronal vulnerability mediated by direct activation of alphaCaMKII transduction pathway in the postsynaptic compartment.
引用
收藏
页码:777 / 786
页数:10
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