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.
Lack of PSD-95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway / F. Gardoni, c. Bellone, B. Viviani, M. Marinovich, E. Meli, D.E. Pellegrini-Giampietro, F. Cattabeni, M.M.G. Di Luca. - In: EUROPEAN JOURNAL OF NEUROSCIENCE. - ISSN 0953-816X. - 16:5(2002), pp. 777-786.
|Titolo:||Lack of PSD-95 drives hippocampal neuronal cell death through activation of an αCaMKII transduction pathway|
GARDONI, FABRIZIO (Primo)
BELLONE, CAMILLA (Secondo)
CATTABENI, FLAMINIO NICOLA (Penultimo)
DILUCA, MONICA MARIA GRAZIA (Ultimo)
|Parole Chiave:||AMPA receptor; NMDA receptor complex; Postsynaptic density; Rat|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2002|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1046/j.1460-9568.2002.02141.x|
|Appare nelle tipologie:||01 - Articolo su periodico|