Activating mGlu(3) Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.
Activating mGlu(3) Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.
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DOI：
10.1016/j.biopsych.2021.02.970
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发表时间：
2021-09-15
影响因子：
10.6
通讯作者：
Conn PJ
中科院分区：
文献类型：
--
作者：
Dogra S;Stansley BJ;Xiang Z;Qian W;Gogliotti RG;Nicoletti F;Lindsley CW;Niswender CM;Joffe ME;Conn PJ
编码mGlu3代谢性谷氨酸受体的基因GRM3的多态性与认知障碍和精神分裂症等神经精神疾病有关。选择性遗传和分子工具的有限可用性阻碍了对mGlu3受体调节突触可塑性和认知的机制的清晰理解。我们检查了有微量恐惧条件作用的小鼠的联想学习，这是一种依赖于海马体的学习任务，在精神分裂症患者中被破坏。使用离体海马切片制剂、选择性药理学工具和选择性基因缺失mGlu3受体在特定神经元亚群中的表达来评估潜在的细胞机制。mGlu3受体激活增强了亚慢性苯环利定诱导的微量恐惧调节和逆转缺陷。机制研究表明，mGlu3受体激活诱导化生改变，通过mGlu5受体依赖、内源性大麻素介导的去抑制机制，偏置传入刺激诱导长期增强。海马锥体细胞中mGlu3或mGlu5的选择性基因缺失消除了mGlu3激活的影响，揭示了mGlu3和mGlu5相互作用增强认知功能的新机制。这些数据表明，激活海马锥体细胞中的mGlu3受体可以通过诱导一种新的元可塑性来调节回路功能，从而增强对照和受损小鼠的海马依赖性认知，从而为GRM3基因变异导致认知缺陷提供了明确的机制。开发正向调节mGlu3受体功能的方法为治疗精神分裂症和其他精神疾病的认知障碍提供了令人鼓舞的新途径。
Polymorphisms in GRM3, the gene encoding the mGlu3 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 mGlu3 receptors regulate synaptic plasticity and cognition. 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 mGlu3 receptor expression in specific neuronal subpopulations. mGlu3 receptor activation enhanced trace fear conditioning and reversed deficits induced by subchronic phencyclidine. Mechanistic studies revealed that mGlu3 receptor activation induced metaplastic changes, biasing afferent stimulation to induce long-term potentiation through a mGlu5 receptor-dependent, endocannabinoid-mediated, disinhibitory mechanism. Selective genetic deletion of either mGlu3 or mGlu5 from hippocampal pyramidal cells eliminated effects of mGlu3 activation, revealing a novel mechanism by which mGlu3 and mGlu5 interact to enhance cognitive function. These data demonstrate that activation of mGlu3 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 mGlu3 receptor function represents an encouraging new avenue for treating cognitive disruption in schizophrenia and other psychiatric diseases.
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影响因子：
17.1
作者：
Finan C;Gaulton A;Kruger FA;Lumbers RT;Shah T;Engmann J;Galver L;Kelley R;Karlsson A;Santos R;Overington JP;Hingorani AD;Casas JP
通讯作者：
Casas JP
影响因子：
4.2
作者：
Bollinger, Katrina A.;Felts, Andrew S.;Lindsley, Craig W.
通讯作者：
Lindsley, Craig W.
影响因子：
64.8
作者：
Ango, F;Prézeau, L;Fagni, L
通讯作者：
Fagni, L
影响因子：
7.3
作者：
Cosford, NDP;Tehrani, L;Varney, MA
通讯作者：
Varney, MA
影响因子：
4.7
作者：
Di Menna L;Joffe ME;Iacovelli L;Orlando R;Lindsley CW;Mairesse J;Gressèns P;Cannella M;Caraci F;Copani A;Bruno V;Battaglia G;Conn PJ;Nicoletti F
通讯作者：
Nicoletti F