Excitotoxic stimulation downregulates the ubiquitin-proteasome system through activation of NMDA receptors in cultured hippocampal neurons

► Glutamate-induced excitotoxicity decreases proteasome activity, particularly in nucleus. ► Extrasynaptic NMDA receptors contribute to the downregulation of proteasome activity. ► OGD impairs proteasome activity by mechanisms dependent on NMDA receptor activation. ► Glutamate-induced excitotoxicity evokes 26S proteasome disassembly. ► Proteasome inhibition induces hippocampal neuronal death.