The transcription factor Npas4 contributes to adolescent development of prefrontal inhibitory circuits, and to cognitive and emotional functions: Implications for neuropsychiatric disorders
The transcription factor Npas4 contributes to adolescent development of prefrontal inhibitory circuits, and to cognitive and emotional functions: Implications for neuropsychiatric disorders
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DOI：
10.1016/j.nbd.2016.12.012
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发表时间：
2017-03
影响因子：
6.1
通讯作者：
R. Shepard;Kelsey A. Heslin;L. Coutellier
中科院分区：
文献类型：
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作者：
R. Shepard;Kelsey A. Heslin;L. Coutellier
青少年大脑的特点是功能和结构的变化，特别是在前额叶皮层（PFC）的抑制系统。这些变化是获得成人认知功能和情绪调节所必需的，这些过程中的损伤与神经病理学如精神分裂症和情感障碍有关。调节这种青少年完善的前额叶抑制回路的分子机制在很大程度上仍然未知。在这里，我们证明了转录因子Npas4在这一过程中发挥了重要作用。在小鼠中使用一系列行为、分子、药理学和遗传学方法，我们证明Npas4缺陷以性别特异性方式影响PFC中GABA能传递的多种标记物（包括小清蛋白和GAD 67）的青春期表达。GABA能标记物的这种异常表达模式与性别特异性认知和情感障碍相关，这些障碍仅在青春期而非青春期后Npas4缺乏开始时发生。最后，我们表明，在青春期使用GABA增强药物丙戊酸钠进行长期治疗足以诱导Npas4缺陷小鼠中观察到的分子和行为异常的长期恢复。总之，我们提供的证据参与转录因子Npas4的结构变化，影响前额叶抑制电路在青春期。进一步研究Npas4在青少年大脑中的作用可能会为青少年时期出现的神经精神疾病的分子机制提供新的见解。
The adolescent brain is marked by functional and structural modifications, particularly within the inhibitory system of the prefrontal cortex (PFC). These changes are necessary for the acquisition of adult cognitive functions and emotion regulation, and impairments in these processes are associated with neuropathologies such as schizophrenia and affective disorders. The molecular mechanisms regulating this adolescent refinement of prefrontal inhibitory circuits remain largely unknown. Here we demonstrate that the transcription factor Npas4 plays a major role in this process. Using a series of behavioral, molecular, pharmacological and genetic approaches in mice, we demonstrate that deficiency in Npas4 affects adolescent expression of multiple markers of GABAergic transmission in the PFC, including parvalbumin and GAD67, in a sex-specific manner. This abnormal pattern of expression of GABAergic markers is associated with sex-specific cognitive and emotional impairments that occur only when Npas4 deficiency begins at adolescence but not post-adolescence. Finally, we show that chronic treatment with the GABA enhancing drug sodium valproate during adolescence is sufficient to induce long-lasting recovery of the molecular and behavioral abnormalities observed in Npas4 deficient mice. Altogether, we provide evidence for the involvement of the transcription factor Npas4 to the structural changes that affect prefrontal inhibitory circuits during adolescence. Further investigations of Npas4 role in the adolescent brain might provide new insights on the molecular mechanisms underlying neuropsychiatric disorders that emerge during adolescence.