HCN通道对MVN神经元内在膜特性的调控是前庭发育及代偿的关键因素

The function of vestibular system is crucial for animal’s advanced features, while vestibular compensation refers to the phenomena of central vestibular recovery from unilateral destruction of peripheral vestibular organs, but the mechanisms is far from clear. Medial vestibular nucleus(MVN) consists of A and B type neurons with significantly identical intrinsic membrane properties. The constitution rate of two type neurons and the changes of response pattern become both of the common pathway and marks of vestibular development and vestibular compensation. In developed animals, MVN neurons initial mainly consisting of A type convert from A to B type which are half to half; whileas, in the compensation course, the constitution of MVN neurons convert to predominant A type neurons in ipsilesional side and predominant B type neurons in contralesional side, but the mechanism that promotes the above-mentioned shifts is unclear now. We have discovered in our preliminary experiments and demonstrated that the key to differentiate B type from A type neuron lies in its activity-dependant HCN channel currents (Ih). Thus, we propose hypothesis that: 1) at the developmental stages, expression of HCN channels increases following the vestibular afflux of stimulus, and promoting the shift from A to B type; 2) in terms of vestibular compensation, MVN neurons respectively up- or down-regulates the expression of HCN channels on ipsilesional and contralesional sides based on modifications of afflux of stimulus resulting from unilateral vestibular destruction and prompting the reversely transition of A/B type neurons, therefore, leading to the rebalance of central response. This projection plans to adopt both normal and HCN gene defected mice, and aims at investigating the relationship between Ih and intrinsic membrane properties and revealing pivotal role of HCN channels playing in vestibular development and compensation.

双侧前庭张力的成熟与协调是维护前庭功能的基础；而前庭代偿是指一侧前庭外周损毁后、中枢恢复平衡的现象。前庭内侧核(MVN)含有A、B两型内在膜特性相异的神经元，两型占比以及基于此的中枢响应模式的转变是实现前庭发育与代偿的共同特征。前庭发育时MVN神经元从普遍A型转变为两型各半，而代偿时损毁侧及健侧分别转变为A型及B型为主，但转变机制不明。我们的预实验发现，活动依赖的HCN通道电流是B型神经元内在膜特性区别于A型的关键，并进而决定神经元响应模式。为此我们提出以下假说：1）在发育期前庭传入刺激下，双侧HCN通道表达增多，改变MVN神经元内在膜特性，促成A型向B型转变；2）在代偿时仅有健侧前庭传入刺激，健侧与毁损侧MVN分别上调和下调HCN通道表达，A、B型分侧逆向转变。申报项目将采用C57及HCN基因缺陷小鼠，证实HCN通道对MVN神经元内在膜特性的调控作用，从探索自然发育着手揭示前庭代偿机制。

自发性放电活动已经被认为是发育早期感觉神经系统的特性之一，即使在感觉传导通路形成之前，机体未能接受外界刺激时，中枢感觉神经元即可出现自发性电活动。这种自发性的电活动参与了突触的形成，神经元的迁移分化等各项生理活动，为形成复杂精细的神经网络提供了生物学基础。在前庭神经系统中，也存在自发性的电活动，并且在发育早期即存在不依赖与外界刺激的自发性电活动。我们的研究发现，在未成熟的前庭内侧核即已表现出自发性电活动，即使在阻断突触传递后，仍可观察到该活动。进一步的研究发现HCN通道作为最主要的起搏器参与了不依赖于突触传递的自发性内源性放电的起搏机制。HCN通道介导Ih电流更强的神经元具有更快的发育特性，而在HCN1-/-小鼠的前庭内侧核神经元中则表现出更加迟缓的发育，这也再次证实了1型HCN通道在前庭内侧核中的主导地位。因此，我们推测这种由HCN1介导的自发性内源性的放电在促进前庭发育、神经网络形成的过程中起到非常重要的作用。此外，我们还发现发育早期的神经元，其自发性放电活动也更易受到胆红素的影响，从而更易导致神经元的兴奋毒性。