Knockdown of Galphaq to model age-related cognitive impairment

描述（由申请人提供）：正常衰老中空间学习能力的下降一直与通过毒蕈碱和代谢型谷氨酸受体-G1 q/11信号转导系统介导的受体信号转导钝化相关。G1 q/11介导的信号传导在学习和记忆中的作用尚未完全确定，主要是由于药理学激动剂对与G1 q/11偶联的受体亚型的非特异性。敲除G1 q或G111（或两者）的转基因小鼠模型已被证明是有问题的，因为运动缺陷或致死性。所提出的模型将通过重组腺相关病毒（rAAV）的递送使用RNA干扰（RNAi）敲低海马中与M1毒蕈碱和I组代谢型谷氨酸受体偶联的占主导地位的G蛋白G1 q。rAAV将使海马中神经元的细胞体变性，抑制内在和投射神经元中的G1 q表达，同时使来自其他核团的传入神经中的G1 q保持完整。这些实验的结果是重要的，因为它们将定义G1 q激活在学习和记忆中的作用，并提供证据证明在衰老中观察到的受体去偶联可能与记忆障碍直接相关，而不仅仅是虚假的相关性。这种分子在空间记忆中的作用的澄清将加强其作为年龄相关记忆障碍的潜在治疗靶点的可能性。铺设说明：该项目将确定在老年学习障碍动物的细胞信号中观察到的某些相关变化是否与记忆力下降直接相关。公共卫生相关性：30%的65岁或以上的人会表现出认知能力下降的迹象，从轻度认知障碍到严重痴呆。本提案中描述的大鼠模型将提供概念证明，即先前在老年学习受损大鼠中观察到的信号改变是由于G蛋白功能的机械变化。这些大鼠研究将提供临床前数据，旨在开发潜在的治疗方法，以抵消正常的、与年龄相关的记忆力下降。

DESCRIPTION (provided by applicant): A decrement in spatial learning ability in normal aging has consistently been correlated with blunted receptor signaling mediated through the muscarinic and metabotropic glutamate receptor-G1q/11 signaling transduction system. The role of G1q/11-mediated signaling in learning and memory is not well established, primarily due to the non-specificity of pharmacological agonists to the receptor subtypes coupled to G1q/11. Transgenic mouse models that knocked out G1q or G111 (or both) have proven to be problematic due to motor deficits or lethality. The proposed model will knock down G1q, the predominate G-protein coupled to the M1 muscarinic and Group I metabotropic glutamate receptors, in the hippocampus using RNA interference (RNAi) via delivery by recombinant adeno-associated virus (rAAV). rAAV will transduce the cell bodies of neurons in the hippocampus, suppressing G1q expression in the intrinsic and projection neurons, while leaving G1q in afferents from other nuclei intact. The results from these experiments are significant in that they will define the role of G1q activation in learning and memory and provide proof that the receptor de-coupling observed in aging may be directly related to memory impairment and not simply a spurious correlation. The clarification of the role that this molecule plays in spatial memory will strengthen its possibility as a potential therapeutic target for age-related memory impairment. Lay description: This project will determine if certain correlational changes observed in cell signaling in the aged, learning impaired animal are directly related to memory decline. PUBLIC HEALTH RELEVANCE: Thirty percent of individuals aged 65 or older will show signs of cognitive decline ranging from mild cognitive impairment to severe dementia. The rat model described in this proposal will provide proof of concept that previously observed signaling alterations in the aged, learning impaired rat are due to mechanistic changes in G-protein function. These rat studies will provide pre-clinical data aimed at the development of potential therapies to counteract normal, age-related memory decline.