Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1
Epistatic and Independent Effects on Schizophrenia-Related Phenotypes Following Co-disruption of the Risk Factors Neuregulin-1 × DISC1
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DOI：
10.1093/schbul/sbw120
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发表时间：
2017
影响因子：
6.6
通讯作者：
C. O’Tuathaigh;F. Fumagalli;L. Desbonnet;Francesc Pérez-Brangulı́;G. Moloney;Samim Loftus;C. O’Leary;Emilie I Petit;Rachel Cox;O. Tighe;G. Clarke;D. Lai;R. Harvey;J. Cryan;K. Mitchell;T. Dinan;M. Riva;J. Waddington
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文献类型：
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作者：
C. O’Tuathaigh;F. Fumagalli;L. Desbonnet;Francesc Pérez-Brangulı́;G. Moloney;Samim Loftus;C. O’Leary;Emilie I Petit;Rachel Cox;O. Tighe;G. Clarke;D. Lai;R. Harvey;J. Cryan;K. Mitchell;T. Dinan;M. Riva;J. Waddington
很少有研究涉及可能的基因×基因（即上位性）相互作用在介导精神分裂症风险中的作用。使用临床前遗传学方法，我们研究了同时破坏危险因素神经调节蛋白-1（NRG 1）和精神分裂症中的破坏1（DISC 1）是否会产生与单独破坏任一基因后观察到的不同的疾病相关表型谱。NRG 1杂合子表现出多动和破坏前脉冲抑制，抗精神病药物治疗逆转，并伴有纹状体多巴胺D2受体蛋白表达减少，社会认知受损，并改变了特定脑区的多巴胺能突触蛋白表达。单基因DISC 1突变体表现出社会认知和筑巢的破坏，改变脑5-羟色胺水平和海马ErbB 4表达，并降低精神分裂症相关microRNA miR-29 b的皮质表达。DISC 1和NRG 1的共破坏，表明上位性，引起了社会性和增强自我梳理的损害，伴随着下丘脑催产素/加压素基因表达的变化。这些发现表明了精神分裂症相关基因NRG 1和DISC 1中DNA变异主要影响下游的特定行为相关性和潜在细胞途径。
Few studies have addressed likely gene × gene (ie, epistatic) interactions in mediating risk for schizophrenia. Using a preclinical genetic approach, we investigated whether simultaneous disruption of the risk factors Neuregulin-1 (NRG1) and Disrupted-in-schizophrenia 1 (DISC1) would produce a disease-relevant phenotypic profile different from that observed following disruption to either gene alone. NRG1 heterozygotes exhibited hyperactivity and disruption to prepulse inhibition, both reversed by antipsychotic treatment, and accompanied by reduced striatal dopamine D2 receptor protein expression, impaired social cognition, and altered glutamatergic synaptic protein expression in selected brain areas. Single gene DISC1 mutants demonstrated a disruption in social cognition and nest-building, altered brain 5-hydroxytryptamine levels and hippocampal ErbB4 expression, and decreased cortical expression of the schizophrenia-associated microRNA miR-29b. Co-disruption of DISC1 and NRG1, indicative of epistasis, evoked an impairment in sociability and enhanced self-grooming, accompanied by changes in hypothalamic oxytocin/vasopressin gene expression. The findings indicate specific behavioral correlates and underlying cellular pathways downstream of main effects of DNA variation in the schizophrenia-associated genes NRG1 and DISC1.