Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism.
Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism.
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DOI：
10.1371/journal.pone.0156082
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Price DJ
中科院分区：
文献类型：
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作者：
Borkowska M;Millar JK;Price DJ
精神分裂症-1基因紊乱（DISC1）与精神分裂症及相关主要精神疾病有关。小鼠Disc1参与大脑发育，主要参与皮层兴奋性神经元的增殖、分化、层压、神经突的生长和突触的形成和维持。本研究研究了小鼠Disc1序列中两个功能缺失点突变（Q31L和L100P）对皮质抑制性中间神经元的影响。这些突变都没有影响中间神经元的总数。然而，100P突变导致感觉皮层表达小白蛋白mRNA和蛋白的中间神经元数量显著减少，而31L突变则没有。为了研究Disc1在调节小白蛋白表达中的作用，我们在小鼠子宫内将野生型或100P突变型的Disc1电穿孔到皮质兴奋性神经元中。野生型Disc1在这些细胞中的过度表达导致电穿孔区及其连接区表达小蛋白的中间神经元密度增加，而Disc1- 100p的表达则没有增加。我们得出结论，100P突变阻止了正常大小的中间神经元表达小白蛋白，皮质兴奋性神经元中Disc1功能的改变间接影响了皮质中间神经元表达小白蛋白，这可能是兴奋性神经元功能输入改变的结果。
Disrupted-in-Schizophrenia-1 (DISC1) gene has been linked to schizophrenia and related major mental illness. Mouse Disc1 has been implicated in brain development, mainly in the proliferation, differentiation, lamination, neurite outgrowth and synapse formation and maintenance of cortical excitatory neurons. Here, the effects of two loss-of-function point mutations in the mouse Disc1 sequence (Q31L and L100P) on cortical inhibitory interneurons were investigated. None of the mutations affected the overall number of interneurons. However, the 100P, but not the 31L, mutation resulted in a significant decrease in the numbers of interneurons expressing parvalbumin mRNA and protein across the sensory cortex. To investigate role of Disc1 in regulation of parvalbumin expression, mouse wild-type Disc-1 or the 100P mutant form were electroporated in utero into cortical excitatory neurons. Overexpression of wild-type Disc1 in these cells caused increased densities of parvalbumin-expressing interneurons in the electroporated area and in areas connected with it, whereas expression of Disc1-100P did not. We conclude that the 100P mutation prevents expression of parvalbumin by a normally sized cohort of interneurons and that altering Disc1 function in cortical excitatory neurons indirectly affects parvalbumin expression by cortical interneurons, perhaps as a result of altered functional input from the excitatory neurons.