Ion channel functions in generation of neural rhythmic activity

我们通过对自发突变或基因敲除小鼠的突触传递和神经元活动的分析，研究了离子通道在产生基本大脑节律活动中的功能作用。离子通道的突变直接或间接地影响神经元电路。产生了N型钙通道基因敲除小鼠。因为N型通道被认为是主要的钙通道，我们预计会出现神经缺陷。但基因敲除的小鼠显然是正常的，没有明显的神经缺陷。他们很有生育能力。然而，详细的研究表明，N型基因敲除小鼠扰乱了由交感神经系统调节的循环稳态。我们研究了P/Q型钙通道突变是如何导致突变小鼠的神经系统症状(小脑性共济失调、失神型发作)(摇摇晃晃、更瘦和打滚)的机制。在突变型小脑性共济失调小鼠中，从平行纤维到浦肯野细胞的突触传递受到损害，损害的程度与共济失调的症状有关。但是，从攀升纤维到浦肯野细胞的突触传递被保留，甚至增强。这些观察结果表明，钙代谢紊乱会导致突触连接的各种变化，并强调了钙在神经活动的发展和维持中的重要作用。我们研究了表现为缺失型癫痫的摇摇欲坠的小鼠的丘脑-皮质联系。我们发现抑制性输入被不成比例地减少。这种输入可能起到前馈抑制系统的作用，以防止大脑皮层过度激活。

We investigated functional roles of ion channels in generating basic brain rhythmic activity, through analyses of synaptic transmission and neuronal activity of spontaneously mutated or knockout mice. Mutations of the ion channels directly or indirectly affect the neuronal circuits.The N-type calcium channel knockout mice were produced. Because the N-type channel was supposed to be the main calcium channel, we expected neurological deficits. But the knockout mice were apparently normal, without visible neurological deficits. They were fertile. Detailed studies, however, revealed that the N-type knockout mice had disturbed circulatory homeostasis which is regulated by the sympathetic nervous system. They may serve as a good model for studying spontaneous hypertension.We investigated the mechanism how the mutations of the P/Q-type calcium channel lead to neurological symptoms (cerebellar ataxia, seizure of absence type) in mutant mice (tottering, leaner, and rolling). In mutant cerebellar ataxic mice, synaptic transmission from parallel fibers to Purkinje cells was impaired, and the degree of the impairment correlated with the symptom of ataxia. However, the synaptic transmission from climbing fibers to Purkinje cells was preserved, or even enhanced. These observations suggest that disturbed calcium metabolism leads to various changes in synaptic connections, and underscores the important role of calcium in the development and maintenance of neural activity.We investigated thalamo-cortical connection in tottering mice which show absence-type seizure. We found that the inhibitory input was disproportionally reduced. This input may function as feed forward inhibition system to prevent the cerebral cortex from hyperactivation.