Morosawa Shunsuke, Iritani Shuji, Fujishiro Hiroshige, Sekiguchi Hirotaka, Torii Youta, Habuchi Chikako, Kuroda Keisuke, Kaibuchi Kozo, Ozaki Norio
Department of Psychiatry, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.
Neuropeptides. 2017 Apr;62:27-35. doi: 10.1016/j.npep.2016.12.010. Epub 2017 Jan 5.
Neuropeptide Y (NPY) has been found to play a critical role in various mental functions as a neurotransmitter and is involved in the development of schizophrenia, a particularly intractable psychiatric disease whose precise etiology remains unknown. Recent molecular biological investigations have identified several candidate genes which may be associated with this disease, including disrupted-in-schizophrenia 1 (DISC1). The role of DISC1 would involve neurogenesis and neuronal migration. However, the functional consequences of this gene defect have not yet been fully clarified in neuronal systems. In the present study, to clarify the neuropathological changes associated with the function of DISC1, we explored how DISC1 dysfunction can induce abnormalities in the NPY neuronal network in the central nervous system. We performed immunohistochemical analyses (including the observation of the distribution and density) of prefrontal cortex specimens from DISC1-knockout (KO) mice, which are considered to be a novel animal model of schizophrenia. We then evaluated the number and size of NPY-immunoreactive (NPY-IR) neurons and the length of NPY-IR fibers. The number of NPY-IR neurons and the length of the fibers were decreased in the prefrontal cortex of DISC1-KO mice. The decrease was particularly prominent in the superficial regions, and the distribution of NPY-IR neurons differed between wild-type and DISC1-KO mice. However, the size of the neurons in the cortices of the DISC1-KO and wild-type mice did not differ markedly. Our findings suggest that dysfunction of DISC1 may lead to the alteration of NPY neurons and neurotransmission issues in NPY-containing neuron systems, which seem to play important roles in both the mental function and neuronal development. DISC1 dysfunction may be involved in the pathogenesis of schizophrenia through the impairment of the NPY neuronal network.
神经肽Y（NPY）作为一种神经递质，已被发现在各种心理功能中起关键作用，并参与精神分裂症的发病过程。精神分裂症是一种特别难以治疗的精神疾病，其确切病因仍然不明。最近的分子生物学研究已经确定了几个可能与这种疾病相关的候选基因，包括精神分裂症相关破坏基因1（DISC1）。DISC1的作用涉及神经发生和神经元迁移。然而，这种基因缺陷在神经元系统中的功能后果尚未完全阐明。在本研究中，为了阐明与DISC1功能相关的神经病理变化，我们探讨了DISC1功能障碍如何诱导中枢神经系统中NPY神经元网络的异常。我们对DISC1基因敲除（KO）小鼠的前额叶皮质标本进行了免疫组织化学分析（包括观察分布和密度），DISC1基因敲除小鼠被认为是一种新型的精神分裂症动物模型。然后我们评估了NPY免疫反应性（NPY-IR）神经元的数量和大小以及NPY-IR纤维的长度。DISC1基因敲除小鼠前额叶皮质中NPY-IR神经元的数量和纤维长度减少。这种减少在表层区域尤为明显，并且野生型和DISC1基因敲除小鼠之间NPY-IR神经元的分布不同。然而，DISC1基因敲除小鼠和野生型小鼠皮质中的神经元大小没有明显差异。我们的研究结果表明，DISC1功能障碍可能导致NPY神经元的改变以及含NPY神经元系统中的神经传递问题，这似乎在心理功能和神经元发育中都起重要作用。DISC1功能障碍可能通过损害NPY神经元网络参与精神分裂症的发病机制。
