Abstracts

Rationale: The ubiquitin proteasome system (UPS) is a principal mediator of synaptic protein degradation, and synaptic UPS capacity responds rapidly to changes in neuronal activity. We tested the hypothesis that acute changes in UPS function would alter the balance between neuronal excitation and inhibition. Methods: To investigate the UPS role in regulating synaptic function, miniature excitatory and inhibitor postsynaptic currents (mEPSCs and mIPSCs) were recorded from cultured hippocampal neurons after varying durations of proteasome inhibition by MG132 or epoximicin. Surface biotinylation was used to examine changes in the surface expression of AMPA and GABA_A receptor subunit subtypes. Results: In cultured hippocampal neurons, within three hours of proteasome inhibition, mEPSC frequency increased markedly, with no change in mEPSC amplitude or kinetics. This was accompanied by a significant increase in the surface expression of the GluR1 AMPA receptor subunit subtype. Over the same time course of proteasome inhibition, mIPSC amplitude increased significantly, with no significant change in mIPSC frequency. Conclusions: Proteasome inhibition differentially regulates AMPA- and GABA_A-mediated postsynaptic currents in hippocampal neurons. This suggests that activity-mediated alterations in UPS function during seizures or epileptogenesis may contribute to changes in neuronal excitability. This work was supported by NIH K08 grant NS048882-01.