激活 mGlu 代谢型谷氨酸受体通过海马内的形质变化适应性挽救精神分裂症样认知缺陷。
Activating mGlu Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.
机构信息
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee.
Vanderbilt University, Nashville, Tennessee.
出版信息
Biol Psychiatry. 2021 Sep 15;90(6):385-398. doi: 10.1016/j.biopsych.2021.02.970. Epub 2021 Mar 6.
BACKGROUND
Polymorphisms in GRM3, the gene encoding the mGlu metabotropic glutamate receptor, are associated with impaired cognition and neuropsychiatric disorders such as schizophrenia. Limited availability of selective genetic and molecular tools has hindered progress in developing a clear understanding of the mechanisms through which mGlu receptors regulate synaptic plasticity and cognition.
METHODS
We examined associative learning in mice with trace fear conditioning, a hippocampal-dependent learning task disrupted in patients with schizophrenia. Underlying cellular mechanisms were assessed using ex vivo hippocampal slice preparations with selective pharmacological tools and selective genetic deletion of mGlu receptor expression in specific neuronal subpopulations.
RESULTS
mGlu receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through an mGlu receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu or mGlu from hippocampal pyramidal cells eliminated effects of mGlu activation, revealing a novel mechanism by which mGlu and mGlu interact to enhance cognitive function.
CONCLUSIONS
These data demonstrate that activation of mGlu receptors in hippocampal pyramidal cells enhances hippocampal-dependent cognition in control and impaired mice by inducing a novel form of metaplasticity to regulate circuit function, providing a clear mechanism through which genetic variation in GRM3 can contribute to cognitive deficits. Developing approaches to positively modulate mGlu receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
背景
编码代谢型谷氨酸受体 mGlu 的基因 GRM3 的多态性与认知障碍和神经精神疾病（如精神分裂症）有关。选择性遗传和分子工具的有限可用性阻碍了人们对 mGlu 受体调节突触可塑性和认知的机制的清晰理解。
方法
我们使用痕迹恐惧条件反射检查了具有这种能力的小鼠的联想学习，这是一种在精神分裂症患者中受损的海马依赖性学习任务。使用选择性药理学工具和特定神经元亚群中 mGlu 受体表达的选择性基因缺失，在体外海马切片制备物中评估了潜在的细胞机制。
结果
mGlu 受体的激活增强了痕迹恐惧条件反射，并逆转了亚慢性苯环利定引起的缺陷。机制研究表明，mGlu 受体的激活诱导了代谢性变化，通过 mGlu 受体依赖性、内源性大麻素介导的、去抑制机制偏向传入刺激以诱导长时程增强。从海马锥体细胞中选择性地缺失 mGlu 或 mGlu 消除了 mGlu 激活的作用，揭示了 mGlu 和 mGlu 相互作用以增强认知功能的新机制。
结论
这些数据表明，在控制和受损的小鼠中，海马锥体细胞中 mGlu 受体的激活通过诱导一种新的代谢性变化来增强海马依赖性认知，从而调节回路功能，为 GRM3 中的遗传变异如何导致认知缺陷提供了明确的机制。开发积极调节 mGlu 受体功能的方法代表了治疗精神分裂症和其他精神疾病认知障碍的一个令人鼓舞的新途径。
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