Cav3.2调控Cdk5激酶活性的机制及其对AD突触和认知功能的影响

阿尔茨海默病(AD)是一种神经退行性疾病，目前很多药物均未能表现出有效的治疗效果；这要求我们开发新思路找到潜在治疗策略。AD的病理过程中，Cdk5过度激活会引起突触功能紊乱，因此精确调控Cdk5活性尤为重要；然而Cdk5的上游调控机制尚不清楚。我们前期研究发现钙离子通道Cav3.2对AMPA/NMDA受体介导的突触传递调控具有Cdk5依赖的特征，表明Cdk5与Cav3.2之间必定存在某种相互作用。此外，谷氨酸能突触传递能够减弱Cdk5激酶活性，且Cav3.2能够门控调节神经递质释放，进一步提示Cav3.2可能是Cdk5活性的调控因子。综上，我们将应用分子细胞生物学，药物学，电生理以及行为学等方法，探讨Cav3.2是否为Cdk5的内源性负调控因子，并通过激活Cav3.2抑制Cdk5活性来改善AD模型鼠突触功能抑制和认知功能障碍，以期为AD的治疗提供全新的策略，开发新的药物靶点。

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive functions. For several decades, it is widely believed that AD is caused by the production of the soluble small peptide beta-amyloid (Aβ) and aggregation of a microtubule-associated protein tau that lead to synaptic losses and dysfunctions. However, many drugs and intervention strategies aimed to block Aβ production or prevent tau aggregation failed to show any positive treatment in preclinical or clinical trials, highlighting the importance and emergence of developing new potential therapeutic strategies. It is well established that Cdk5 hyper-activation results in synaptic dysfunctions, which are implicated in the early pathogenesis of AD. Thus, precise regulation of Cdk5 activity is quite important for the maintenance of synaptic integrity. Nonetheless, the molecular mechanisms underlying the regulation of Cdk5 activity are not well understood. T-type calcium channel Cav3.2 controls AMPA-R and NMDA-R-mediated glutamatergic neurotransmission at central synapses, in which Cdk5 also plays a similar role. More importantly, our preliminary data showed that Cav3.2 controls evoked AMPA and NMDA responses in a Cdk5-dependent manner, suggesting a novel unidentified crosstalk between Cav3.2 and Cdk5 signaling in the regulation of synaptic transmission. In this regard, it is noteworthy that glutamatergic excitatory neurotransmission reduces Cdk5 activity through the enhancement of proteasome-dependent degradation of p35. Moreover, Cav3.2 activation gates excitatory neurotransmitter release, making Cav3.2 a promising candidate that can modulate Cdk5 kinase activity. Therefore, here we hypothesize that Cav3.2 is an endogenous negative regulator of Cdk5 activity and Cav3.2 activation ameliorates synaptic depressions in AD models through suppression of Cdk5 activity.