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.