Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia.
Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia.
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使用新型 mGluR2 激动剂/mGluR3 拮抗剂化合物 LY395756 进行青少年治疗，可逆转精神分裂症神经发育模型中成人的学习缺陷和认知灵活性障碍
DOI：
10.1016/j.nlm.2017.02.004
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发表时间：
2017-04
影响因子：
2.7
通讯作者：
Gao WJ
中科院分区：
文献类型：
--
作者：
Li ML;Gulchina Y;Monaco SA;Xing B;Ferguson BR;Li YC;Li F;Hu XQ;Gao WJ
精神分裂症(SCZ)是一种神经发育性精神障碍，其认知功能在疾病的早期阶段被破坏。虽然认知障碍的机制尚不清楚，但前额叶皮质(PFC)中的N-甲基-D-天冬氨酸受体(NMDAR)功能低下已被发现。此外，SCZ的认知症状通常对目前的抗精神病药物治疗没有反应，到发病时，主宰症状的是多巴胺系统的破坏，而不是NMDAR功能低下。因此，在早期阶段治疗认知缺陷是一个现实的方法。在这项研究中，我们测试了针对mGluR2的早期治疗是否能有效地改善SCZ的甲基氮氧基甲醇醋酸酯(MAM)模型的认知障碍。我们研究了mGluR2激动剂/mGluR3拮抗剂LY395756(LY39)对幼年大鼠NMDAR表达和功能的影响，以及幼年治疗后成年大鼠的认知障碍。我们发现，孕期MAM暴露导致幼年大鼠PFC中NMDAR亚单位NR2B的总蛋白水平显著降低，而pNR2BTyr1472的总蛋白水平显著增加。LY39对幼年MAM暴露大鼠的治疗有效地恢复了受损的NMDAR表达。此外，对暴露于MAM的幼年大鼠进行亚慢性LY39治疗，也可以减轻成年大鼠的学习缺陷和认知灵活性损害，这些障碍是在基于交叉迷宫的集合转移任务中进行的。因此，我们的研究表明，在SCZ的早期阶段使用mGluR2激动剂靶向功能障碍的NMDAR可能是一种有效的策略，除了改善SCZ的认知障碍外，还可以预防SCZ的发生和发展。
Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ.
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影响因子：
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作者：
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