Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia
Altered motor activity, exploration and anxiety in heterozygous neuregulin 1 mutant mice: implications for understanding schizophrenia
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DOI：
10.1111/j.1601-183x.2006.00298.x
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发表时间：
2007-10-01
影响因子：
2.5
通讯作者：
Schofield, P. R.
中科院分区：
文献类型：
--
作者：
Karl, T.;Duffy, L.;Schofield, P. R.
人类遗传学研究表明，神经调节蛋白1（NRG1）是精神分裂症的潜在易感基因。 Nrg1 影响各种神经发育过程，这些过程可能与精神分裂症相关。精神分裂症的神经发育理论表明，遗传和环境因素之间的相互作用是导致精神分裂症的生化改变的原因。为了研究这些相互作用并将实验设计与精神分裂症的病理生理学相匹配，我们在不同的饲养条件和年龄组的杂合 Nrg1 跨膜域突变小鼠模型 (Nrg1 HET) 中应用了针对运动活动、探索和焦虑的综合行为表型策略。我们在 Nrg1 HET 中观察到与运动和探索相关的过度活跃表型。年龄的增加具有运动和探索抑制作用，这种作用在突变小鼠中显着减弱。环境丰富（EE）对运动和探索有刺激性影响。 EE 的影响在 Nrg1 亚型中更为明显。我们的研究还显示 Nrg1 HET 具有中度任务特异性抗焦虑样表型，该表型受到外部因素的影响。在杂合Nrg1突变小鼠中检测到的行为表型并不是精神分裂症本身所特有的，但突变小鼠对外源因素的敏感性增加与精神分裂症的病理生理学和神经发育理论一致。我们的研究结果强调了仔细控制外部因素实验设计和全面、综合表型分析策略的重要性。因此，Nrg1 HET 可能与其他遗传和药物模型相结合，有助于阐明精神分裂症背后的病理生理机制。
Human genetic studies have shown that neuregulin 1 (NRG1) is a potential susceptibility gene for schizophrenia. Nrg1 influences various neurodevelopmental processes, which are potentially related to schizophrenia. The neurodevelopmental theory of schizophrenia suggests that interactions between genetic and environmental factors are responsible for biochemical alterations leading to schizophrenia. To investigate these interactions and to match experimental design with the pathophysiology of schizophrenia, we applied a comprehensive behavioural phenotyping strategy for motor activity, exploration and anxiety in a heterozygous Nrg1 transmembrane domain mutant mouse model (Nrg1 HET) using different housing conditions and age groups. We observed a locomotion- and exploration-related hyperactive phenotype in Nrg1 HETs. Increased age had a locomotion- and exploration-inhibiting effect, which was significantly attenuated in mutant mice. Environmental enrichment (EE) had a stimulating influence on locomotion and exploration. The impact of EE was more pronounced in Nrg1 hypomorphs. Our study also showed a moderate task-specific anxiolytic-like phenotype for Nrg1 HETs, which was influenced by external factors. The behavioural phenotype detected in heterozygous Nrg1 mutant mice is not specific to schizophrenia per se, but the increased sensitivity of mutant mice to exogenous factors is consistent with the pathophysiology of schizophrenia and the neurodevelopmental theory. Our findings reinforce the importance of carefully controlling experimental designs for external factors and of comprehensive, integrative phenotyping strategies. Thus, Nrg1 HETs may, in combination with other genetic and drug models, help to clarify pathophysiological mechanisms behind schizophrenia.