O'Tuathaigh C M P, Babovic D, O'Sullivan G J, Clifford J J, Tighe O, Croke D T, Harvey R, Waddington J L
Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland.
Neuroscience. 2007 Jun 15;147(1):18-27. doi: 10.1016/j.neuroscience.2007.03.051. Epub 2007 May 21.
Neuregulin-1 (NRG1) has been identified as a candidate susceptibility gene for schizophrenia. In the present study the functional role of the NRG1 gene, as it relates to cognitive and social processes known to be disrupted in schizophrenia, was assessed in mice with heterozygous deletion of transmembrane (TM)-domain NRG1 in comparison with wildtypes (WT). Social affiliative behavior was assessed using the sociability and preference for social novelty paradigm, in terms of time spent in: (i) a chamber containing an unfamiliar conspecific vs. an empty chamber (sociability), or (ii) a chamber containing an unfamiliar conspecific vs. a chamber containing a familiar conspecific (preference for social novelty). Social dominance and aggressive behavior were examined in the resident-intruder paradigm. Spatial learning and memory were assessed using the Barnes maze paradigm, while spatial working memory was measured using the continuous variant of the spontaneous alternation task. Barnes maze data revealed intact spatial learning in NRG1 mutants, with elevated baseline latency to enter the escape hole in male NRG1 mutants reflecting an increase in activity level. Similarly, although a greater number of overall arm entries were found, spontaneous alternation was unaffected in NRG1 mice. Social affiliation data revealed NRG1 mutants to evidence a specific loss of WT preference for spending time with an unfamiliar as opposed to a familiar conspecific. This suggests that NRG1 mutants show a selective impairment in response to social novelty. While spatial learning and working memory processes appear intact, heterozygous deletion of TM-domain NRG1 was associated with disruption to social novelty behavior. These data inform at a novel phenotypic level on the functional role of this gene in the context of its association with risk for schizophrenia.
神经调节蛋白-1（NRG1）已被确定为精神分裂症的候选易感基因。在本研究中，与野生型（WT）小鼠相比，对跨膜（TM）结构域NRG1杂合缺失的小鼠评估了NRG1基因的功能作用，该作用与已知在精神分裂症中受到破坏的认知和社会过程相关。使用社交性和对社交新奇性范式的偏好来评估社交亲和行为，具体依据在以下方面花费的时间：（i）一个装有陌生同种个体的小室与一个空小室相比（社交性），或（ii）一个装有陌生同种个体的小室与一个装有熟悉同种个体的小室相比（对社交新奇性的偏好）。在居住者-入侵者范式中检查社会支配和攻击行为。使用巴恩斯迷宫范式评估空间学习和记忆，而使用自发交替任务的连续变体测量空间工作记忆。巴恩斯迷宫数据显示NRG1突变体的空间学习完好无损，雄性NRG1突变体进入逃生洞的基线潜伏期延长，反映出活动水平增加。同样，尽管发现总的手臂进入次数更多，但NRG1小鼠的自发交替不受影响。社交亲和数据显示NRG1突变体表现出与野生型相比，在与陌生而非熟悉同种个体相处时间上的特定偏好丧失。这表明NRG1突变体在对社交新奇性的反应中表现出选择性损伤。虽然空间学习和工作记忆过程似乎完好无损，但TM结构域NRG1的杂合缺失与社交新奇行为的破坏有关。这些数据在新的表型水平上说明了该基因在与精神分裂症风险相关背景下的功能作用。
