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

项目概要/摘要 这项建议代表了一个高度创新的研究路线，重点是了解机制/s PHF 21 B（植物同源结构域指蛋白21 B）缺陷会损害社会记忆。社会 可能存在于多种精神障碍中的损伤的特征是缺乏 社会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 和中风我们提出了概念上的新证据，表明PHF 21 B缺乏显着损害 社会记忆在三腔社会互动测试中，PHF 21 B的社会偏好指数 缺陷小鼠没有显着差异，但他们花更多的时间与新的陌生人互动， 与熟悉的陌生人相比，野生型小鼠。因此，他们的社会新奇指数是 显著高于野生型动物，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损伤。我们的新数据也支持 PHF 21 B与表观遗传标记三甲基化Lys 36在组蛋白H3（H3 K36 me 3）结合的概念， 与表达基因体相关的组蛋白标记物， 剪接和DNA修复。拟议的研究将询问PHF 21 B在神经元中的特定作用。 与社会行为相关的功能，特别是在社会认知障碍方面。预期成果是 研究PHF 21 B在海马中的作用，并鉴定其靶基因和调控基因。 与社会记忆有关的机制。我们希望这些研究将提供新的见解 研究影响社会认同的表观遗传变化的细胞和分子机制 记忆该项目产生的结果具有转化潜力，因为它们可以促进 社会记忆缺陷的新药理学靶点的开发。

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.