Dissecting the roles of an epigenetic regulator of genes involved in synaptic plasticity and social cognition.

项目摘要/摘要 这项建议代表了一条专注于理解机制的高度创新的研究路线/S PHF21B(植物同源结构域指蛋白21B)缺乏会损害社会记忆。社交 损害，可能出现在多种精神障碍中，其特征是 社交功能。社会认知障碍是几种神经退行性疾病的中心特征， 神经精神障碍和神经发育障碍，如自闭症谱系和注意力缺陷 多动症。它们也经常发生在创伤性脑损伤后的急性脑损伤之后。 还有中风。我们提出了概念上的新证据，表明PHF21B缺乏显著损害 社会记忆。在三室社交测验中，PHF21B的社会偏好指数 有缺陷的小鼠没有显著差异，但它们花在与新陌生人互动的时间比 与熟悉的陌生人相比，野鼠。因此，他们的社会新颖性指数是 明显大于野生动物，表明社会记忆缺陷。社会记忆 使用5次试验的社会记忆测试进一步证实了损伤。我们的新数据也支持 PHF21B与组蛋白H3(H3K36me3)的表观遗传标记三甲基化Lys36结合的概念，a 与转录相关的表达基因体和新兵蛋白相关的组蛋白标记物， 剪接和DNA修复。拟议的研究将询问PHF21B在神经元中的具体作用(S) 与社会行为相关的功能，特别是在社会认知障碍方面。预期结果是 研究PHF21B在海马区的作用并确定其靶基因和调控基因 与社会记忆相关的机制。我们期望拟议的研究将提供新的见解。 影响社会认知的表观遗传变化背后的细胞和分子机制 记忆。该项目将产生的结果具有翻译潜力，因为它们可能有助于 针对社会记忆缺陷的新药理靶点的开发。

PROJECT SUMMARY/ABSTRACT This proposal represents a highly innovative line of research focused on understanding the mechanism/s by which PHF21B (plant homeodomain finger protein 21B) deficiency impairs social memory. Social impairments, which may be present in multiple psychiatric disorders, are characterized by deficiencies in social functioning. Social cognitive impairments are a central feature of several neurodegenerative, neuropsychiatric, and neurodevelopmental disorders, such as autism spectrum and attention deficit hyperactivity disorder. They also frequently occur following acute brain damage after traumatic brain injury and stroke. We present conceptually novel evidence showing that PHF21B deficiency significantly impairs social memory. In the three-chamber social interaction test, the social preference index of the PHF21B deficient mice did not significantly differ, but they spent more time interacting with the new stranger than with the familiar stranger compared to wild-type mice. Therefore, their social novelty index was significantly greater than wild-type animals, suggesting social memory deficits. Social memory impairments were further confirmed using the 5-trial social memory test. Our new data also support the concept that PHF21B binds to the epigenetic marker tri-methylated Lys36 at histone H3 (H3K36me3), a histone marker associated with expressed gene bodies and recruits proteins implicated in transcription, splicing, and DNA repair. The proposed studies will interrogate the specific role(s) of PHF21B in neuronal function relevant to social behaviors, specifically in social recognition impairment. Expected outcomes are to characterize the role of PHF21B in the hippocampus and identify its target genes and regulatory mechanisms relevant to social memory. We expect that the proposed studies will provide novel insights into the cellular and molecular mechanisms underlying epigenetic changes that affect social recognition memory. The results to be generated by this project have translational potential as they may facilitate the development of novel pharmacological targets for social memory deficits.