Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Neuron. 2010 Feb 25;65(4):480-9. doi: 10.1016/j.neuron.2010.01.019.
Adult brain function and behavior are influenced by neuronal network formation during development. Genetic susceptibility factors for adult psychiatric illnesses, such as Neuregulin-1 and Disrupted-in-Schizophrenia-1 (DISC1), influence adult high brain functions, including cognition and information processing. These factors have roles during neurodevelopment and are likely to cooperate, forming pathways or "signalosomes." Here we report the potential to generate an animal model via in utero gene transfer in order to address an important question of how nonlethal deficits in early development may affect postnatal brain maturation and high brain functions in adulthood, which are impaired in various psychiatric illnesses such as schizophrenia. We show that transient knockdown of DISC1 in the pre- and perinatal stages, specifically in a lineage of pyramidal neurons mainly in the prefrontal cortex, leads to selective abnormalities in postnatal mesocortical dopaminergic maturation and behavioral abnormalities associated with disturbed cortical neurocircuitry after puberty.
成人的大脑功能和行为受发育过程中神经元网络形成的影响。成人精神疾病的遗传易感因素，如 Neuregulin-1 和精神分裂症相关蛋白 1（DISC1），影响包括认知和信息处理在内的成人高级大脑功能。这些因素在神经发育过程中起作用，并且可能合作形成途径或“信号体”。在这里，我们报告了通过宫内基因转移产生动物模型的潜力，以解决一个重要问题，即早期发育中的非致命性缺陷如何影响出生后的大脑成熟和成年后的高级大脑功能，而各种精神疾病（如精神分裂症）中都存在这些功能缺陷。我们发现，DISC1 在产前和围产期的短暂敲低，特别是在前额皮质中的主要锥体神经元谱系中，会导致青春期后出现中脑多巴胺能成熟和与皮质神经回路紊乱相关的行为异常的选择性异常。
