The nucleosome is the fundamental unit of the genome that organizes DNA and is made of four histone proteins: H2A, H2B, H3, and H4. Regulation of histone proteins affects gene expression through multiple mechanisms, including exchange with histone variants. While variants of H2A and H3 have well defined roles in chromatin regulation, widely expressed variants of H2B remain elusive. Further, while recent findings link histone variants to neurological disorders, few are well-studied in the context of the brain. The work described here combines multiomic analyses, mouse models, and animal behavior with molecular and biochemical techniques from the chromatin biology field. Using these tools, we reveal broad expression of the H2B variant H2BE in multiple tissues, including in the brain where it is enriched at neuronal promoters. We show that incorporation of H2BE dramatically enhances chromatin accessibility, an effect driven by a single amino acid that lies at the interface between H2BE and nucleosomal DNA. Further, we show that H2BE is critical for synaptic gene expression and long-term memory. Lastly, we show that H2BE expression is activity-dependent, and that H2BE is required for long-term activity-dependent transcriptional responses. Together, these data reveal a novel epigenetic mechanism through which neurons translate environmental inputs into changes to the chromatin landscape which in turn alter gene expression and ultimately govern animal behavior.