Premium
Lack of PSD‐95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway
Author(s) -
Gardoni Fabrizio,
Bellone Camilla,
Viviani Barbara,
Marinovich Marina,
Meli Elena,
PellegriniGiampietro Domenico E.,
Cattabeni Flaminio,
Di Luca Monica
Publication year - 2002
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2002.02141.x
Subject(s) - ampa receptor , hippocampal formation , cnqx , microbiology and biotechnology , glutamatergic , nmda receptor , nbqx , ryanodine receptor , postsynaptic density , postsynaptic potential , neuroscience , biology , glutamate receptor , excitatory postsynaptic potential , chemistry , endoplasmic reticulum , inhibitory postsynaptic potential , receptor , biochemistry
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 αCaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of αCaMKII 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 αCaMKII transduction pathway in the postsynaptic compartment.