In the current study we present evidence suggesting that PARP-1 regulates neurogenesis and its deficiency may result in schizophrenia-like behavioral deficits in mice. PARP-1 knockout neural stem cells exhibited a marked upregulation of embryonic stem cell phosphatase that can suppress the proliferative signaling of PI3K-Akt and ERK. The suppressed activity of Akt and ERK in the absence of PARP-1 results in the elevation of FOXO1 activity and its downstream target genes p21 and p27, leading to the inhibition of neural stem cell proliferation. Moreover, expression of neurogenic factors and neuronal differentiation were decreased in the PARP-1 knockout neural stem cells whereas glial differentiation was increased. In accordance with the in vitro data, PARP-1 knockout mice exhibited reduced brain weight with enlarged ventricle as well as decreased adult neurogenesis in the hippocampus. Interestingly, PARP-1 knockout mice exhibited schizophrenia-like symptoms such as anxiety, depression, social interaction deficits, cognitive impairments, and prepulse inhibition deficits. Taken together, our results suggest that PARP-1 regulates neurogenesis during development and in adult and its absence may lead to the schizophrenia-like behavioral abnormality in mice.

中文翻译：

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PARP-1缺陷小鼠的神经发生缺陷和精神分裂症样行为。

在当前的研究中，我们提供证据表明PARP-1调节神经发生，其缺乏可能导致小鼠精神分裂症样行为缺陷。PARP-1基因敲除的神经干细胞表现出明显的胚胎干细胞磷酸酶上调，可以抑制PI3K-Akt和ERK的增殖信号。在缺少PARP-1的情况下，Akt和ERK的活性受到抑制，导致FOXO1活性及其下游靶基因p21和p27升高，从而导致神经干细胞增殖受到抑制。此外，在PARP-1敲除的神经干细胞中神经原性因子的表达和神经元分化减少，而神经胶质分化增加。根据体外数据，PARP-1基因敲除小鼠的脑重量减少，脑室增大，海马的成年神经发生减少。有趣的是，PARP-1基因敲除小鼠表现出精神分裂症样症状，如焦虑，抑郁，社交互动障碍，认知障碍和前冲抑制障碍。两者合计，我们的研究结果表明PARP-1调节发育和成年期间的神经发生，并且它的缺失可能导致小鼠精神分裂症样行为异常。