Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, China; Key Laboratory of Addiction Research of Zhejiang Province, Ningbo 315010, PR China.
Department of Pharmacology, Ningbo University School of Medicine, 818 Fenghua Rd, Ningbo, Zhejiang, 315211, China.
Neuropharmacology. 2020 Oct 15;177:108231. doi: 10.1016/j.neuropharm.2020.108231. Epub 2020 Jul 18.
Juvenile social isolation (SI) and neglect have a negative impact on neurodevelopment persistently, which is associated with cognitive dysfunction in neurodevelopmental disorders. Given the critical role of metabotropic glutamate receptors (mGluRs) in synaptic homeostasis of the prefrontal cortex (PFC), pharmacological intervention on mGluRs has been attempted in order to improve cognitive dysfunction in animal models of neurodevelopmental disorder, as well as in clinical trials. Here we examined the effects of the mGluR2/3 antagonist LY341495 on prefrontal synaptic transmission, spatial working memory, and recognition memory in adult C57BL/6J mice that experienced juvenile SI. We found that SI-reared mice exhibited working memory impairment and decreased excitatory presynaptic release probability of pyramidal neurons in the medial PFC compared with group-reared mice. The positive effect of LY341495 on excitatory synaptic transmission in SI-reared mice was more prominent than the effect in group-reared mice. A single treatment with mGluR2/3 antagonist LY341495 significantly improved the performance of SI-reared mice in the Y-maze test but not in the novel object recognition (NOR) test, while repeated treatments were effective in both tasks. These findings suggest that enhancing glutamatergic transmission via inhibition of mGluR2/3 signaling might represent a promising strategy for improving cognitive function in neurodevelopmental disorders.
青少年社交隔离（SI）和忽视会对神经发育产生持久的负面影响，这与神经发育障碍中的认知功能障碍有关。鉴于代谢型谷氨酸受体（mGluRs）在前额叶皮层（PFC）的突触稳态中起着关键作用，因此人们试图通过药物干预 mGluRs 来改善神经发育障碍动物模型以及临床试验中的认知功能障碍。在这里，我们研究了 mGluR2/3 拮抗剂 LY341495 对经历过青少年 SI 的成年 C57BL/6J 小鼠前额叶突触传递、空间工作记忆和识别记忆的影响。我们发现，与群居小鼠相比，SI 饲养的小鼠表现出工作记忆障碍和内侧 PFC 锥体神经元的兴奋性突触前释放概率降低。与群居小鼠相比，LY341495 对 SI 饲养小鼠兴奋性突触传递的积极影响更为明显。单次 mGluR2/3 拮抗剂 LY341495 处理可显著改善 SI 饲养小鼠在 Y 迷宫测试中的表现，但不能改善新物体识别（NOR）测试中的表现，而重复处理在这两种任务中均有效。这些发现表明，通过抑制 mGluR2/3 信号增强谷氨酸能传递可能是改善神经发育障碍认知功能的一种有前途的策略。
