Department of Neurologic Surgery, Mayo Clinic, Rochester, Minnesota.
Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Hippocampus. 2020 Jul;30(7):715-723. doi: 10.1002/hipo.23195. Epub 2020 Feb 14.
Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2-null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2-null state may affect the function of the hippocampus. In this study, adult PC2-null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2-null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field-excitatory postsynaptic potentials (EPSP), long-term potentiation (LTP), and paired-pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2-null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2-null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2-null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2-null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2-null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2-null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.
前激素转化酶 2（PC2）是许多神经肽生物合成所必需的，包括海马中的几种神经肽。在缺乏具有酶活性的 PC2（PC2 缺失）的小鼠脑中，许多神经肽以其前体或中间形式积累。关于 PC2 缺失状态如何影响海马功能知之甚少。在这项研究中，成年 PC2 缺失小鼠及其野生型（WT）同窝仔鼠分别接受了三项分析，以确定在正常和应激条件下，PC2 缺失与生理、行为和分子水平相关的可能变化。通过海马切片的电生理记录测量诱发的场兴奋性突触后电位（EPSP）、长时程增强（LTP）和成对脉冲易化（PPF）。进行 Morris 水迷宫（MWM）测试以检查指示海马完整性的行为变化。使用定量质谱分析来确定海马蛋白质组在对局部脑缺血损伤的反应中的变化。我们发现，PC2 缺失和 WT 动物之间诱发 EPSP 的阈值没有显着差异。然而，在 PC2 缺失小鼠中观察到 LTP 在触发率和幅度上均增加，表明 PC2 可能参与调节突触强度。另一方面，PPF 在 PC2 缺失小鼠中显示出降低，表明存在突触前机制。与 LTP 的变化一致，PC2 缺失小鼠在 MWM 测试中找到逃生平台的潜伏期缩短。此外，在远端局灶性脑缺血后，WT 和 PC2 缺失小鼠的海马蛋白质组均发生变化，与神经传递、胞吐和运输过程相关的蛋白质明显变化，而在 PC2 缺失但不在 WT 小鼠中可见。总之，我们的结果表明 PC2 参与调节海马突触可塑性、学习和记忆行为，以及源自大脑其他区域的应激对海马的反应。
