Knockdown of Galphaq to model age-related cognitive impairment

描述(申请人提供)：正常衰老时空间学习能力的下降一直与毒碱和代谢性谷氨酸受体-G1q/11信号转导系统介导的钝化受体信号有关。G1q/11介导的信号在学习和记忆中的作用尚未得到很好的证实，主要是由于药物激动剂对与G1q/11偶联的受体亚型的非特异性。敲除G1q或G111(或两者)的转基因小鼠模型已被证明存在运动缺陷或致死性问题。所提出的模型将通过重组腺相关病毒(RAAV)通过RNA干扰(RNAi)在海马区击倒G1q，G1q是主要的G蛋白，与M1毒碱受体和I组代谢性谷氨酸受体偶联。RAAV将转导海马神经元的胞体，抑制固有神经元和投射神经元中G1q的表达，而保持其他核团传入神经元中的G1q不变。这些实验的结果意义重大，因为它们将定义G1q激活在学习和记忆中的作用，并提供证据表明，在衰老过程中观察到的受体去偶联可能与记忆损害直接相关，而不仅仅是虚假的相关性。阐明该分子在空间记忆中的作用将增强其作为年龄相关性记忆损害潜在治疗靶点的可能性。这个项目将确定在衰老、学习障碍的动物中观察到的细胞信号的某些相关变化是否与记忆衰退直接相关。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症。这项建议中描述的大鼠模型将提供概念证据，证明先前在老年学习障碍大鼠中观察到的信号变化是由于G蛋白功能的机械性变化。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、与年龄相关的记忆衰退。

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.