Chromatin refers to the complex of DNA and histone proteins (H2A, H2B, H3, and H4). This complex organizes the genome and plays a vital role in controlling gene expression and overall cellular state. Recent work has highlighted the importance of chromatin in the brain in biological mechanisms like learning and memory, and neurological diseases. In addition, chromatin regulation is critical in development, controlling cellular responses to the environment, and aging. Chromatin is regulated through several mechanisms, including incorporating histone variants into nucleosomes in place of canonical histones. There are a limited number of well characterized histone variants, and many still have unknown functions and mechanisms of regulation. Recent findings defined the first broadly expressed H2B variant, H2BE, and demonstrated that it regulates chromatin structure, neuronal transcription, and mouse behavior. However, the role of H2BE in other cell types and its role throughout the lifespan remain unknown. Here, we discovered that H2BE is enriched in astrocytes in the brain and accumulates with age in both astrocytes and neurons. Using single-nucleus RNA-sequencing, we demonstrate that H2BE promotes synaptic gene expression in neurons and astrocytes in young brains. Using microelectrode array recordings, we discovered that H2BE is required in both cell types for proper synaptic function. In aging brains, loss of H2BE similarly affects synaptic genes in neurons and dampens some age-related transcriptional changes in astrocytes and neurons. Lastly, behavioral testing demonstrates that H2BE loss disrupts long-term memory but improves working memory in aging mice. These data provide novel links between histone variants, age-related gene expression changes in astrocytes and neurons, and memory.