TAF15 overexpression impairs memory in mice by inhibiting the transcription of Npas4

TAF15, a DNA and RNA-binding protein primarily localized in the nucleus, has been reported to be associated with the aging process and neurodegenerative diseases accompanied by cognitive decline. However, its role in regulating learning and memory remains unclear. Here, we discovered that TAF15 accumulates in the hippocampus of aged mice, and TAF15 overexpressing in hippocampal neurons led to spatial learning and memory impairments in young mice. These finding are further supported by the significant reduction of dendritic spines density and synaptic proteins level. Further studies revealed that overexpression of TAF15 is likely to reduce the number of dendritic spines by inhibiting the expression of Npas4 (among the most rapidly induced immediate-early genes) and its target gene Nptx2. Notably, the expression of Npas4 and Nptx2 in the hippocampus of aged mice is also downregulated. Additionally, we demonstrated that TAF15 binds to the core promoter of Npas4 gene and inhibits its transcription, and neuronal depolarization induces the dissociation of TAF15 from Npas4 promoter. Together, these findings uncover a direct role of TAF15 in regulating spatial learning and memory formation, which may provide new insights into aging-related cognitive deficits.