Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior. In this study, we show that selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task. We further found that striatal GluD1 is preferentially found in dendritic shafts, and more frequently associated with thalamic than cortical glutamatergic terminals suggesting localization to projections from the thalamic parafascicular nucleus (Pf). Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. Optogenetic studies demonstrated functional changes at thalamostriatal synapses from the Pf, but no effect on the corticostriatal system, upon ablation of GluD1 in the dorsal striatum. These studies suggest a novel molecular mechanism by which genetic variations associated with neuropsychiatric disorders may impair behavioral flexibility, and reveal a unique principle by which GluD1 subunit regulates forebrain circuits.

中文翻译：

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纹状体谷氨酸delta-1受体调节行为的灵活性和丘脑基底连接性。

行为灵活性和重复行为受损是自闭症和其他神经精神疾病的常见表型，但对潜在的突触机制了解甚少。对突触形成/维持至关重要的反式突触谷氨酸-δ（GluD）-Cerebellin 1-Neurexin复合物代表了神经精神疾病的脆弱轴。我们以前已经发现，GluD1缺失会导致逆向学习缺陷和重复行为。在这项研究中，我们表明选择性消融背纹状体的GluD1损害了水T迷宫任务中的行为灵活性。我们进一步发现，纹状体GluD1优先在树突状干中发现，与丘脑相关的比皮层谷氨酸能的终末更常见，提示局限在丘脑束旁核（Pf）的投影。从纹状体中有条件地删除GluD1导致了丘脑（而非皮层）末端的选择性丢失，并降低了谷氨酸能神经传递。光遗传学研究表明，在消融背侧纹状体中的GluD1后，Pf的丘脑纹状体突触的功能发生了变化，但对皮质纹状体系统没有影响。这些研究提出了一种新的分子机制，通过该机制，与神经精神疾病相关的遗传变异可能损害行为灵活性，并揭示了GluD1亚基调节前脑回路的独特原理。消融背侧纹状体中的GluD1后，对皮质口系统无影响。这些研究提出了一种新的分子机制，通过该机制，与神经精神疾病相关的遗传变异可能损害行为灵活性，并揭示了GluD1亚基调节前脑回路的独特原理。消融背侧纹状体中的GluD1后，对皮质口系统无影响。这些研究提出了一种新的分子机制，通过该机制，与神经精神疾病相关的遗传变异可能损害行为灵活性，并揭示了GluD1亚基调节前脑回路的独特原理。