Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post‐synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder
Aberrant cognitive phenotypes and altered hippocampal BDNF expression related to epigenetic modifications in mice lacking the post‐synaptic scaffolding protein SHANK1: Implications for autism spectrum disorder
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DOI：
10.1002/hipo.22741
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发表时间：
2017-05
期刊：
影响因子：
3.5
通讯作者：
A. Sungur;M. Jochner;Hani Harb;A. Kılıç;H. Garn;R. Schwarting;M. Wöhr
中科院分区：
文献类型：
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作者：
A. Sungur;M. Jochner;Hani Harb;A. Kılıç;H. Garn;R. Schwarting;M. Wöhr
自闭症谱系障碍(ASD)是一类神经发育障碍，其特征是持续性的社会交流/互动障碍，以及受限/重复的行为模式。ASD是最易遗传的神经精神疾病之一，虽然现有证据表明存在一系列复杂的遗传因素，但Shank基因家族已成为最有希望的候选之一。在这里，我们评估了与ASD相关的表型，特别强调了社会行为和认知在Shank1小鼠突变体中的表现，并与杂合型和野生型对照鼠的性别发育进行了比较。虽然社会接近行为在所有实验条件下都很明显，社会再认只受到基因的轻微影响，但Shank1−/−缺失突变小鼠在物体再认记忆中受到严重损害。这种影响在青少年中尤其明显，并不是由于物体辨别能力受损，而是在独立的小鼠队列中重复出现。在神经生物学水平上，Shank1−/−小鼠海马区脑源性神经营养因子蛋白表达的增加与物体识别缺陷平行；然而，脑源性神经营养因子水平在基线条件下没有差异。因此，我们研究了海马区脑源性神经营养因子表达的表观遗传调控的变化，并在Shank1−/−小鼠的脑源性神经营养因子启动子1处检测到组蛋白H3乙酰化的丰富，这与学习相关的脑源性神经营养因子的增加一致。总之，我们的发现表明，Shank1的缺失导致了一种异常的认知表型，其特征是对象识别记忆的严重损害和海马区BDNF水平的增加，这可能是由于表观遗传修饰所致。这一结果支持ASD和智力残疾之间的联系，并建议表观遗传调控作为潜在的治疗靶点。
Autism spectrum disorder (ASD) is a class of neurodevelopmental disorders characterized by persistent deficits in social communication/interaction, together with restricted/repetitive patterns of behavior. ASD is among the most heritable neuropsychiatric conditions, and while available evidence points to a complex set of genetic factors, the SHANK gene family has emerged as one of the most promising candidates. Here, we assessed ASD‐related phenotypes with particular emphasis on social behavior and cognition in Shank1 mouse mutants in comparison to heterozygous and wildtype littermate controls across development in both sexes. While social approach behavior was evident in all experimental conditions and social recognition was only mildly affected by genotype, Shank1−/− null mutant mice were severely impaired in object recognition memory. This effect was particularly prominent in juveniles, not due to impairments in object discrimination, and replicated in independent mouse cohorts. At the neurobiological level, object recognition deficits were paralleled by increased brain‐derived neurotrophic factor (BDNF) protein expression in the hippocampus of Shank1−/− mice; yet BDNF levels did not differ under baseline conditions. We therefore investigated changes in the epigenetic regulation of hippocampal BDNF expression and detected an enrichment of histone H3 acetylation at the Bdnf promoter1 in Shank1−/− mice, consistent with increased learning‐associated BDNF. Together, our findings indicate that Shank1 deletions lead to an aberrant cognitive phenotype characterized by severe impairments in object recognition memory and increased hippocampal BDNF levels, possibly due to epigenetic modifications. This result supports the link between ASD and intellectual disability, and suggests epigenetic regulation as a potential therapeutic target.