Ablation of neuropsin-neuregulin 1 signaling imbalances ErbB4 inhibitory networks and disrupts hippocampal gamma oscillation.
Ablation of neuropsin-neuregulin 1 signaling imbalances ErbB4 inhibitory networks and disrupts hippocampal gamma oscillation.
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DOI：
10.1038/tp.2017.20
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发表时间：
2017-03-07
影响因子：
6.8
通讯作者：
Tamura H
中科院分区：
文献类型：
--
作者：
Kawata M;Morikawa S;Shiosaka S;Tamura H
表达小白蛋白的中间神经元对于健康大脑中的信息处理至关重要，而这些功能的协调在患病大脑中受到严重破坏。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，由神经蛋白酶驱动的神经调节蛋白 1 (NRG1)-ErbB4 信号传导对于协调大脑可塑性非常重要。 Neuropsin 响应长期增强或抑制而裂解成熟的 NRG1（与细胞外糖胺聚糖结合），释放出可激活其受体 ErbB4 的可溶性配体。在这里，我们在小鼠中发现，红藻氨酸诱导的癫痫持续状态短暂地提高了神经蛋白酶的蛋白水解活性，并随着时间的推移刺激 cFos 表达，这表明表达 ErbB4 和小白蛋白的中间神经元的激活遵循锥体神经元的兴奋和随后的沉默。在神经蛋白缺陷小鼠中，红藻氨酸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，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），导致癫痫持续状态的进展。神经蛋白酶缺陷小鼠的伽玛振荡缓慢但不快，显示出功率降低。脑室内输注可溶性NRG1配体部分可将E/I平衡、癫痫持续状态和γ振荡恢复至正常水平。这些结果表明，神经蛋白酶-NRG1信号系统通过调节表达小清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，并且神经蛋白酶通过NRG1-ErbB4向表达小清蛋白的中间神经元信号传导来调节E/I平衡和γ振荡。该神经元系统可能是针对认知障碍的药物治疗的有用靶标。
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.