Lysine Crotonylation Acts as an Epigenetic Switch for Glutamate Neurotransmission and Spatial Memory

Using a single-nucleus multiomics approach, this study demonstrates that enhancing histone lysine crotonylation modulates cell type–specific chromatin accessibility and drives the expression of genes encoding key proteins involved in glutamatergic neurotransmission during memory consolidation. Overall design: To study the impact of crotonate administration on memory enhancement, mice were trained in Spatial Object Recognition (SOR) task using a sub-threshold training paradigm, and oral administration of crotonate (200 mg/kg) or vehicle (Saline) was given immediately after the completion of the training trials. 1hr after crotonate administration, the dorsal hippocampus was harvested, and nuclei were isolated for single nuclei multiomics. We performed multiomic sequencing (snRNA-seq + snATAC-seq) obtained from the dorsal hippocampus of 2 groups (Crotonate1+Crotonate2 vs. Saline1+Saline2). Chromatin Immunoprecipitation followed by sequencing (ChIP-Seq) was performed using a pan-Kcr antibody on the dorsal hippocampus tissue from the mice that were either housed in homecage or trained in the SOR task.