Potentiate Cav3.3 To Treat Cognitive Deficits Associated with Impaired Sleep Spindle

项目总结/摘要 睡眠纺锤波是发生在NREM（非快速眼动）睡眠中的标志性脑振荡， 内丘脑皮层离线处理脉冲是12-15赫兹振荡的增强和减弱的脉冲 起源于丘脑网状核（TRN），当其神经元经历爆发性放电时，TRN- 丘脑继电器网络通过相互连接以主轴频率振荡。睡眠纺锤波是 在精神分裂症患者和阿尔茨海默病患者中显著降低，这是两种非常不同的CNS疾病 然而，两者都显示出与认知障碍相关的显著改变的睡眠纺锤体特性。我们 假设功能减退的TRN可能是这两种毁灭性疾病的风险/症状的基础。 CACNA 1 I是CaV3.3电压依赖性钙通道α1功能核心的编码蛋白，其表达与CaV3.3电压依赖性钙通道α1功能核心的表达密切相关。 富含TRN。我们已经发现了两种新的化学支架，可以增强CaV3.3的功能， 该提案旨在递送体内现成的Cav3.3阳性调节剂。这一多学科的努力预计将 产生一组尖锐的药理学试剂，以增强CaV3.3在大脑中的功能，并提名 用于治疗精神分裂症患者认知障碍的临床前开发的候选物。

Project Summary/Abstract Sleep spindle is a hallmark brain oscillation occurring in NREM (non-rapid eye movement) sleep that reflect intrinsic thalamocortical offline processing. Spindles are waxing and waning bursts of 12-15 Hz oscillations that originate in Thalamic Reticular Nucleus (TRN) when its neurons undergo bursting firing, and TRN- Thalamic Relay network oscillates at spindle frequency through the reciprocal connection. Sleep spindles are markedly reduced in schizophrenia patients as well as in Alzheimer patients, two very different CNS disorders yet both demonstrated significant altered sleep spindle properties associated with cognitive impairment. We hypothesize that hypofunctional TRN may underlie the risk/symptoms of these two devasting illnesses. CACNA1I is encode the α1 functional core of the CaV3.3 voltage-ˇgated calcium channels, and its expression is enriched in TRN. We have discovered two novel chemical scaffolds that potentiate CaV3.3 function, and this proposal aims to deliver in vivo ready Cav3.3 positive modulators. This multidisciplinary effort is expected to yield a panel of incisive pharmacological reagents to enhance CaV3.3 function in the brain and nominate candidates for preclinical development for treating cognitive impairments in schizophrenia patients.