Eells J B, Misler J A, Nikodem V M
National Institute for Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 900 Rockville Pike, Bethesda, MD 20892, USA.
Neuroscience. 2006 Jul 21;140(4):1117-26. doi: 10.1016/j.neuroscience.2005.12.065. Epub 2006 May 9.
Sensorimotor gating is a phenomenon that is linked with dopamine neurotransmission in limbic and cortical areas, and disruption of sensorimotor gating has been consistently demonstrated in schizophrenia patients. The nuclear receptor Nurr1 is essential for development of dopamine neurons and, using Nurr1-null heterozygous mice, has been found to be important for normal dopamine neurotransmission as null heterozygous mice have reduced limbic and cortical dopamine levels and elevated open-field locomotor activity. The current investigation compared sensorimotor gating, as measured by prepulse inhibition of the acoustic startle response, in Nurr1 wild-type and null heterozygous mice. When mice were weaned between 19 and 21 days of age either into isolation or groups of three to five and tested 12 weeks later, prepulse inhibition was elevated in group-raised null heterozygous mice and significantly disrupted in isolated null heterozygous mice as compared with isolation-raised wild-type mice and group-raised null heterozygous mice. Isolation had no effect on prepulse inhibition in wild-type mice. Isolation reduced tissue dopamine levels and elevated dopamine turnover in the nucleus accumbens and striatum in both wild-type and null heterozygous mice. In the prefrontal cortex, isolation reduced dopamine and 3,4-dihydroxyphenylacetic acid levels in null heterozygous as compared with isolation-raised wild-type mice, whereas no differences were observed between group-raised wild-type and null heterozygous mice. Neither the null heterozygous genotype nor isolation had any effect on basal or stress-induced corticosterone levels. These data suggest that the Nurr1 null heterozygous genotype predisposes these mice to isolation-induced disruption of prepulse inhibition that may be related to the interactions between intrinsic deficiencies in dopamine neurotransmission as a result of the null heterozygous genotype and isolation-induced changes in dopamine neurotransmission. Post-weaning isolation of Nurr1 null heterozygous mice provides a model to explore the interactions of genetic predisposition and environment/neurodevelopment on dopamine function that has important relevance to neuropsychiatric disorders.
感觉运动门控是一种与边缘系统和皮质区域的多巴胺神经传递相关的现象，并且在精神分裂症患者中一直存在感觉运动门控的破坏。核受体Nurr1对多巴胺神经元的发育至关重要，利用Nurr1基因敲除杂合小鼠发现，它对正常的多巴胺神经传递很重要，因为基因敲除杂合小鼠的边缘系统和皮质多巴胺水平降低，旷场运动活动增加。当前的研究比较了Nurr1野生型和基因敲除杂合小鼠的感觉运动门控，感觉运动门控通过对听觉惊吓反应的前脉冲抑制来测量。当小鼠在19至21日龄断奶后，要么单独饲养，要么三到五只一组饲养，并在12周后进行测试时，与单独饲养的野生型小鼠和群居饲养的基因敲除杂合小鼠相比，群居饲养的基因敲除杂合小鼠的前脉冲抑制增强，而单独饲养的基因敲除杂合小鼠的前脉冲抑制则显著受损。单独饲养对野生型小鼠的前脉冲抑制没有影响。单独饲养会降低野生型和基因敲除杂合小鼠伏隔核和纹状体中的组织多巴胺水平，并提高多巴胺周转率。在额叶前皮质中，与单独饲养的野生型小鼠相比，单独饲养会降低基因敲除杂合小鼠中的多巴胺和3,4-二羟基苯乙酸水平，而群居饲养的野生型和基因敲除杂合小鼠之间未观察到差异。基因敲除杂合基因型和单独饲养对基础或应激诱导的皮质酮水平均无任何影响。这些数据表明，Nurr1基因敲除杂合基因型使这些小鼠易受单独饲养诱导的前脉冲抑制破坏，这可能与基因敲除杂合基因型导致的多巴胺神经传递内在缺陷与单独饲养诱导的多巴胺神经传递变化之间的相互作用有关。Nurr1基因敲除杂合小鼠断奶后的单独饲养提供了一个模型，用于探索遗传易感性与环境/神经发育对多巴胺功能的相互作用，这与神经精神疾病具有重要相关性。
