Umemori Juzoh, Takao Keizo, Koshimizu Hisatsugu, Hattori Satoko, Furuse Tamio, Wakana Shigeharu, Miyakawa Tsuyoshi
Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo Kutsukake-cho, Toyoake 470-1192, Japan.
BMC Res Notes. 2013 May 21;6:203. doi: 10.1186/1756-0500-6-203.
The Grin1 (glutamate receptor, ionotropic, NMDA1) gene expresses a subunit of N-methyl-D-aspartate (NMDA) receptors that is considered to play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. Grin1 is a candidate susceptibility gene for neuropsychiatric disorders, including schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). In our previous study, we examined an N-ethyl-N-nitrosourea (ENU)-generated mutant mouse strain (Grin1(Rgsc174)/Grin1+) that has a non-synonymous mutation in Grin1. These mutant mice showed hyperactivity, increased novelty-seeking to objects, and abnormal social interactions. Therefore, Grin1(Rgsc174)/Grin1+ mice may serve as a potential animal model of neuropsychiatric disorders. However, other behavioral characteristics related to these disorders, such as working memory function and sensorimotor gating, have not been fully explored in these mutant mice. In this study, to further investigate the behavioral phenotypes of Grin1(Rgsc174)/Grin1+ mice, we subjected them to a comprehensive battery of behavioral tests.
There was no significant difference in nociception between Grin1(Rgsc174)/Grin1+ and wild-type mice. The mutants did not display any abnormalities in the Porsolt forced swim and tail suspension tests. We confirmed the previous observations that the locomotor activity of these mutant mice increased in the open field and home cage activity tests. They displayed abnormal anxiety-like behaviors in the light/dark transition and the elevated plus maze tests. Both contextual and cued fear memory were severely deficient in the fear conditioning test. The mutant mice exhibited slightly impaired working memory in the eight-arm radial maze test. The startle amplitude was markedly decreased in Grin1(Rgsc174)/Grin1+ mice, whereas no significant differences between genotypes were detected in the prepulse inhibition (PPI) test. The mutant mice showed no obvious deficits in social behaviors in three different social interaction tests.
This study demonstrated that the Grin1(Rgsc174)/Grin1+ mutation causes abnormal anxiety-like behaviors, a deficiency in fear memory, and a decreased startle amplitude in mice. Although Grin1(Rgsc174)/Grin1+ mice only partially recapitulate symptoms of patients with ADHD, schizophrenia, and bipolar disorder, they may serve as a unique animal model of a certain subpopulation of patients with these disorders.
Grin1（谷氨酸受体，离子型，NMDA1）基因表达N-甲基-D-天冬氨酸（NMDA）受体的一个亚基，该亚基被认为在兴奋性神经传递、突触可塑性和大脑发育中起重要作用。Grin1是包括精神分裂症、双相情感障碍和注意力缺陷多动障碍（ADHD）在内的神经精神疾病的候选易感基因。在我们之前的研究中，我们检测了一种由N-乙基-N-亚硝基脲（ENU）诱导产生的突变小鼠品系（Grin1(Rgsc174)/Grin1+），其Grin1基因存在一个非同义突变。这些突变小鼠表现出多动、对物体的新奇探索增加以及社交互动异常。因此，Grin1(Rgsc174)/Grin1+小鼠可能作为神经精神疾病的潜在动物模型。然而，这些突变小鼠中与这些疾病相关的其他行为特征，如工作记忆功能和感觉运动门控，尚未得到充分研究。在本研究中，为了进一步探究Grin1(Rgsc174)/Grin1+小鼠的行为表型，我们对它们进行了一系列全面的行为测试。
Grin1(Rgsc174)/Grin1+小鼠与野生型小鼠在伤害感受方面没有显著差异。突变体在波索尔特强迫游泳和悬尾试验中未表现出任何异常。我们证实了之前的观察结果，即这些突变小鼠在旷场试验和家笼活动试验中的运动活性增加。它们在明暗转换试验和高架十字迷宫试验中表现出异常的焦虑样行为。在恐惧条件反射试验中，情境性和线索性恐惧记忆均严重受损。突变小鼠在八臂放射状迷宫试验中表现出轻微的工作记忆受损。Grin1(Rgsc174)/Grin1+小鼠的惊吓幅度明显降低，而在预脉冲抑制（PPI）试验中未检测到基因型之间的显著差异。在三种不同的社交互动试验中，突变小鼠在社交行为方面没有明显缺陷。
本研究表明，Grin1(Rgsc174)/Grin1+突变导致小鼠出现异常的焦虑样行为、恐惧记忆缺陷和惊吓幅度降低。尽管Grin1(Rgsc174)/Grin1+小鼠仅部分重现了ADHD、精神分裂症和双相情感障碍患者的症状，但它们可能作为这些疾病特定亚群患者的独特动物模型。
