Chronic administration of non-constitutive proteasome inhibitor modulates plasticity in hippocampus following tetanic stimulation, but not short theta-burst stimulation.

Proteasomes degrade most intracellular proteins. Several different forms of proteasomes are known. Proteasome inhibitors targeting different proteasome forms are used in clinical practice and were shown to modulate long-term potentiation (LTP) in hippocampal slices of untreated animals. Here we studied the effect of chronic administration of non-constitutive proteasome inhibitor ONX-0914 on the LTP induced by two different protocols: tetanic stimulation and theta-burst stimulation (TBS). Excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from control animals and animals treated with DMSO or ONX-0914 were compared. The TBS stimulation did not change LTP kinetics in hippocampal slices, however chronic administration of ONX-0914 led to the decrease in fEPSP slopes after tetanic stimulation. Observed effects correlated with differential expression of genes involved in synaptic plasticity, glutaminergic synapse and synaptic signaling. Obtained results indicate that non-constitutive proteasomes are likely involved in the tetanus-evoked LTP but not the LTP occurring after TBS, supporting the relevance and complexity of the role of proteasomes in the synaptic plasticity. Overall design: deep RNA sequencing of hyppocampus tissues of mice treated with immunoproteasome inhibitor ONX-0914