SFRS8 Regulates Memory by Modulating RNA Splicing of Synaptic Genes.

SFRS8, a member of the serine and arginine-rich (SR) protein family, functions as a splicing factor and is highly expressed in the brain. Despite its abundance, its specific role in the brain has remained unclear. Here, we show that SFRS8 is critical for maintaining normal synaptic protein levels and synaptic density. Mechanistically, SFRS8 binds to SF3B3, a key component of the U2 snRNP complex, to regulate alternative RNA splicing. Specifically, SFRS8 regulates the association of Psd95 pre-mRNA with the U2 snRNP complex and subsequent exon 18 skipping in Psd95, thereby controlling PSD95 protein levels. Knockdown of SFRS8 in the hippocampus reduces synaptic protein expression, decreases dendritic spine density, and impairs memory in mice. Consistent with these in vivo findings, SFRS8 depletion in cultured neurons also leads to lower synaptic protein levels and reduced synaptic density. Taken together, our results demonstrate that SFRS8 regulates memory function in mice by modulating the alternative splicing and expression of synaptic genes through its interaction with SF3B3, a core component of the U2 snRNP complex.