Schizophrenia: a tale of two critical periods for prefrontal cortical development.
Schizophrenia: a tale of two critical periods for prefrontal cortical development.
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DOI：
10.1038/tp.2015.115
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发表时间：
2015-08-18
影响因子：
6.8
通讯作者：
Zecevic N
中科院分区：
文献类型：
--
作者：
Selemon LD;Zecevic N
精神分裂症是一种大脑发育异常的疾病。现在有相当多的证据表明，环境因素在精神分裂症中起着致病作用。该病发病率的升高与产前环境中的各种干扰以及青少年时期的社会因素和药物摄入有关。在这里，我们研究了妊娠前三个月和青春期前额叶皮层的神经发育，以进一步了解精神分裂症中可能脆弱的神经发育过程。前额叶皮层的早期胚胎发育以细胞增殖为特征，包括祖细胞的更新、早期瞬时细胞群的产生和皮层下细胞群的神经发生。动物模型显示，减少妊娠早期细胞增殖会在前额皮质产生类似精神分裂症的病理，并模仿该疾病的关键行为和认知症状。另一方面，兴奋性突触的消除是青春期前额叶皮层成熟过程中发生的基本过程。提高压力的不良社会环境会增加中皮质通路的多巴胺刺激，并可能导致青春期突触修剪过度。在非人类灵长类动物模型中，多巴胺过度刺激已被证明会降低前额叶锥体细胞脊柱密度，并与严重的认知功能障碍有关。前额叶皮层发育在妊娠早期和青春期末期是精神分裂症易感性的两个关键时期，细胞增殖和突触消除可能分别受到环境因素的影响。
Schizophrenia is a disease of abnormal brain development. Considerable evidence now indicates that environmental factors have a causative role in schizophrenia. Elevated incidence of the disease has been linked to a wide range of disturbances in the prenatal environment and to social factors and drug intake during adolescence. Here we examine neurodevelopment of the prefrontal cortex in the first trimester of gestation and during adolescence to gain further insight into the neurodevelopmental processes that may be vulnerable in schizophrenia. Early embryonic development of the prefrontal cortex is characterized by cell proliferation, including renewal of progenitor cells, generation of early transient cell populations and neurogenesis of subcortical populations. Animal models show that curtailing early gestational cell proliferation produces schizophrenia-like pathology in the prefrontal cortex and mimics key behavioral and cognitive symptoms of the disease. At the other end of the spectrum, elimination of excitatory synapses is the fundamental process occurring during adolescent maturation in the prefrontal cortex. Adverse social situations that elevate stress increase dopamine stimulation of the mesocortical pathway and may lead to exaggerated synaptic pruning during adolescence. In a non-human primate model, dopamine hyperstimulation has been shown to decrease prefrontal pyramidal cell spine density and to be associated with profound cognitive dysfunction. Development of the prefrontal cortex in its earliest stage in gestation and in its final stage in adolescence represents two critical periods of vulnerability for schizophrenia in which cell proliferation and synaptic elimination, respectively, may be influenced by environmental factors.