Sungur A Özge, Jochner Magdalena C E, Harb Hani, Kılıç Ayşe, Garn Holger, Schwarting Rainer K W, Wöhr Markus
Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Marburg, Germany.
Institute of Laboratory Medicine and Pathobiochemistry-Molecular Diagnostics, Philipps-University of Marburg, Marburg, Germany.
Hippocampus. 2017 Aug;27(8):906-919. doi: 10.1002/hipo.22741. Epub 2017 May 29.
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.
自闭症谱系障碍（ASD）是一类神经发育障碍，其特征是社交沟通/互动持续存在缺陷，以及行为模式受限/重复。ASD是遗传性最强的神经精神疾病之一，虽然现有证据指向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基因之一。在这里，我们评估了与ASD相关的表型，特别关注Shank1基因敲除小鼠在发育过程中的社交行为和认知能力，并与杂合子和野生型同窝对照进行比较，涵盖了两性。虽然在所有实验条件下都观察到了社交接近行为，且社交识别仅受到基因型的轻微影响，但Shank1基因敲除小鼠在物体识别记忆方面严重受损。这种影响在幼年小鼠中尤为明显，并非由于物体辨别能力受损，并且在独立的小鼠群体中得到了重复验证。在神经生物学水平上，Shank1基因敲除小鼠海马体中脑源性神经营养因子（BDNF）蛋白表达增加，与物体识别缺陷平行；然而在基线条件下BDNF水平并无差异。因此，我们研究了海马体BDNF表达的表观遗传调控变化，发现在Shank1基因敲除小鼠的Bdnf启动子1处组蛋白H3乙酰化富集，这与学习相关的BDNF增加一致。总之，我们的研究结果表明，Shank1基因缺失导致了一种异常的认知表型，其特征是物体识别记忆严重受损以及海马体BDNF水平升高，这可能是由于表观遗传修饰所致。这一结果支持了ASD与智力残疾之间的联系，并表明表观遗传调控是一个潜在的治疗靶点。
