Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice
Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice
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DOI：
10.1002/npr2.12073
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发表时间：
2019-09-01
影响因子：
2.5
通讯作者：
Miyakawa, Tsuyoshi
中科院分区：
文献类型：
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作者：
Nakajima, Ryuichi;Takao, Keizo;Miyakawa, Tsuyoshi
目的：突触 Ras GTP 酶激活蛋白 1 (SYNGAP1) 通过 AMPA 受体运输调节突触可塑性。在患有智力障碍 (ID) 和自闭症谱系障碍 (ASD) 的人类患者中发现了 SYNGAP1 突变。几乎每个患有 SYNGAP1 相关 ID 的人都会患上癫痫症，其中大约 50% 患有自闭症谱系障碍 (ASD)。据估计，与 SYNGAP1 相关的 ID 至少占 ID 病例的 1%。据报道，在携带 Syngap1 突变的小鼠模型中，存在严重的认知和情感功能障碍，但一些研究结果并不一致。为了进一步了解 SYNGAP1 基因的行为意义，我们使用行为测试组评估了 Syngap1 杂合突变小鼠的各个行为领域。 方法：对 Seth Grant 小组创建的 Syngap1 基因杂合突变的雄性小鼠（Syngap1(-/-) 小鼠）进行一系列综合行为测试，检查一般健康状况以及神经系统筛查、旋转棒、热板、开放视野、明/暗转换、升高plus 迷宫、社交互动、前脉冲抑制、Porsolt 强迫游泳、尾部悬挂、步态分析、T 迷宫、Y 迷宫、Barnes 迷宫、情境和提示恐惧条件反射以及家庭笼运动活动。为了控制由于多重假设检验导致的 I 型错误，低于由 Benjamini-Hochberg 方法计算的错误发现率的 P 值被认为是研究范围内具有统计显着性。 结果：Syngap(-1/+) 小鼠表现出运动活性增加、前脉冲抑制减少以及工作和参考空间记忆受损，与之前的研究一致。 Syngap1 突变小鼠的情景恐惧记忆受损和惊吓反射增加的情况无法重现。在 Syngap1(-/+) 小鼠中观察到对疼痛刺激的敏感性显着降低和运动功能受损。尽管运动活动增加是这些表型的潜在混杂因素，但注意到焦虑样行为和抑郁样行为减少。家笼运动活动的增加表明不仅在特定的行为测试条件下而且在熟悉的环境中都具有过度运动活动。结论：在Syngap1（-/-）小鼠中，我们可以重现大多数先前报道的认知和情绪缺陷。我们在 Syngap1(-/+) 小鼠中发现对疼痛刺激的敏感性降低和运动功能受损，这与 SYNGAP 相关 ID 患者的共同特征一致。我们进一步证实 Syngap1 杂合子小鼠重现了 ID 和 ASD 患者的症状。
Aims: Synaptic Ras GTPase-activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1-related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1-related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery.Methods: Male mice with a heterozygous mutation in the Syngap1 gene (Syngap1(-/-)mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T-maze, Y-maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple-hypothesis testing, P-values below the false discovery rate calculated by the Benjamini-Hochberg method were considered as study-wide statistically significant.Results: Syngap(-1/+) mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1(-/+) mice. Decreased anxiety-like behavior and depression-like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments.Conclusion: In Syngap1(-/-) mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1(-/+) mice are consistent with the common characteristics of patients with SYNGAP-related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.