Kalirin 7 在雌激素调节海马神经元可塑性中的作用

The hippocampus is a center for learning and memory as well as a target of diseases. Dendritic spines are the substrates of ifelong information processing and memory storage. The formation of dendritic spines and excitatory synapses in hippocampal neurons is regulated by estrogen, but the underlying mechanisms remain unclear. Kalirin (Kal)7 is exclusively localized to the postsynaptic side of excitatory synapses. Expression of exogenous Kal7 increases spine density whereas reduced endogenous Kal7 decreases spine density in hippocampal neurons in vitro. Kal7 is required for synaptic structure and function in CA1 neurons in Kal7 knockout (Kal7KO) mice. Our previous work shows that Kal7 immunoreactivity and its protein in hippocampal neurons are regulated by estrogen in vivo and in vitro. However , it is not yet clear whether estrogen regulates Kal7 expression at the transcriptional (mRNA) or post-transcriptional level. The pathways through which estrogen regulates Kal7 expression are not understood. Our hypothesis is that Kal7 plays a key role in the mechanisms by which estrogen regulates spine formation and synaptic plasticity. Aims of this proposal are: 1). study how estrogen regulates Kal7 expression in the hippocampus. 2) Determine whether Kal7 plays an essential in estrogen-mediated spine formation and synaptic functions. 3) Determine the pathways through which estrogen regulates Kal7 expression. The results of this research will extend our understanding of estrogen-mediated synaptic plasticity, hopefully facilitating development of therapies to treat menopausal symptoms and facilitate learning and memory. A better understanding of the roles of Kal7 in estrogen-induced spine formation will contribute to our ability to optimize the beneficial effects of estrogen without causing undesired side effects.

神经树突棘是长期的信息处理和贮存记忆的物质基础。雌激素（E2）调节海马神经元树突棘和兴奋性突触的形成，但是基本机制尚未了解。Kalirin７ (Kal7)在海马神经元兴奋性突触的突触后独特地表达。海马神经细胞Kal7过度表达可增加树突棘密度，而降低内源性的Kal7则减少树突棘密度。Kal7基因敲除（Kal7/KO）表明，CA1区Kal7是维持突触结构与功能必需的。海马神经元内的Kal7蛋白受E2调节。然而，E2是否能调节Kal7mRNA尚不清楚。E2调节Kal7表达的机制也不知道。我们的假说是Kal7在E2调节树突棘形成和突触的可塑性过程中起关键性作用。本计划的目标是：１）研究E2如何增加Kal7在海马细胞中的表达。２）确定Kal7是否在E2调节树突棘形成和增强突触功能的过程中是不可缺少的。３）寻找E2调节Kal7表达的分子机制。这项研究的结果将加深对E2调节树突棘形成突触的可塑性的理解。

本项目结合行为学研究了雌激素与海马神经元可塑性变化的关系及其机制，证明了外周雌激素与海马雌激素的关系，发现卵巢摘除后海马雌激素水平较外周相对稳定，以及海马雌激素动态变化的过程，海马雌激素是调节海马神经可塑性及动物行为的关键；首次证明了雄性大鼠海马雌激素在神经可塑性调节和情绪行为调节中具有重要作用；证明BDNF-TrkBR是雌激素调节海马神经元可塑性变化的路径之一，尤其是TrkB的位置至关重要；Kalirin-7是雌激素调节神经元结构可塑性和突触结构与功能可塑性的关键分子；海马神经元及突触功能可塑性变化主要表现在5-HT和谷氨酸能突触的变化，其中谷氨酸NMDAR和AMPAR亚基的变化，以及谷氨酸与r-氨基丁酸的平衡是功能可塑性的重要基础；发现了雌激素调节神经活动可能与Klotho表达有关。海马神经元可塑性变化参与了情绪行为和认知功能的调节。这些研究结果对于解释和理解女性绝经后情绪行为和认知功能变化，以及雌激素替代治疗的时间节点控制具有重要意义；对应激性抑郁发生的5-HT学说及其单胺类学说、谷氨酸学说与神经可塑性学说的内在联系有了新的认识；对于认知能力下降和老年痴呆的治疗提供理论依据和新思路。