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. deep RNA sequencing of hyppocampus tissues of mice treated with immunoproteasome inhibitor ONX-0914

蛋白酶体（proteasome）可降解绝大多数细胞内蛋白质。目前已发现多种不同形式的蛋白酶体。靶向不同蛋白酶体亚型的蛋白酶体抑制剂已应用于临床实践，且被证实可调控未处理动物海马脑片的长时程增强（long-term potentiation, LTP）。本研究探讨了长期给予非组成型蛋白酶体抑制剂ONX-0914对两种不同刺激范式——强直刺激（tetanic stimulation）与θ爆发式刺激（theta-burst stimulation, TBS）——诱导的长时程增强的影响。我们对比分析了对照组、二甲基亚砜（DMSO）处理组及ONX-0914处理组小鼠的海马脑片的场兴奋性突触后电位（field excitatory postsynaptic potentials, fEPSPs）。结果显示，θ爆发式刺激未改变海马脑片的长时程增强动力学过程，但长期给予ONX-0914会导致强直刺激后的场兴奋性突触后电位斜率下降。观测到的上述效应与参与突触可塑性（synaptic plasticity）、谷氨酸能突触及突触信号转导的基因差异表达具有相关性。本研究结果表明，非组成型蛋白酶体可能参与强直刺激诱发的长时程增强，但不参与θ爆发式刺激诱导的长时程增强，这佐证了蛋白酶体在突触可塑性中作用的相关性与复杂性。对经免疫蛋白酶体抑制剂ONX-0914处理的小鼠海马组织开展深度RNA测序（deep RNA sequencing）。