Kawata M, Morikawa S, Shiosaka S, Tamura H
Laboratory of Functional Neuroscience, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Nara, Japan.
Department of Pharmacology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan.
Transl Psychiatry. 2017 Mar 7;7(3):e1052. doi: 10.1038/tp.2017.20.
Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)-ErbB4 signaling, which is actuated by neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation-inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the neuropsin-NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that neuropsin regulates E/I balance and gamma oscillations through NRG1-ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.
表达小白蛋白的中间神经元对健康大脑中的信息处理至关重要，而在患病大脑中这些功能的协调会受到严重破坏。海马体中的这些中间神经元如何参与病理功能仍不清楚。我们之前报道过，由神经胰蛋白酶激活的神经调节蛋白1（NRG1）-表皮生长因子受体4（ErbB4）信号传导对于协调大脑可塑性很重要。神经胰蛋白酶会响应长时程增强或抑制作用切割成熟的NRG1（与细胞外糖胺聚糖结合），释放出一种可溶性配体，该配体可激活其受体ErbB4。在此，我们在小鼠中发现，海藻酸诱导的癫痫持续状态会短暂提高神经胰蛋白酶的蛋白水解活性，并刺激cFos表达，其时间进程表明，表达ErbB4和小白蛋白的中间神经元的激活发生在锥体神经元兴奋及随后的沉默之后。在缺乏神经胰蛋白酶的小鼠中，给予海藻酸会损害信号传导，并破坏海马网络中的神经元兴奋-抑制平衡（E/I平衡），这是通过降低小白蛋白阳性中间神经元的活性，同时增加锥体神经元的活性实现的，从而导致癫痫持续状态的进展。缺乏神经胰蛋白酶的小鼠中，慢波而非快波γ振荡的功率降低。脑室内注入可溶性NRG1配体部分可将E/I平衡、癫痫持续状态和γ振荡恢复到正常水平。这些结果表明，神经胰蛋白酶-NRG1信号系统通过调节表达小白蛋白的中间神经元的活性，在颞叶癫痫的病理过程中发挥作用，并且神经胰蛋白酶通过朝向表达小白蛋白的中间神经元的NRG1-ErbB4信号传导来调节E/I平衡和γ振荡。这个神经元系统可能是针对认知障碍的药物治疗的一个有用靶点。
