SFRS8 regulates memory by modulating pre-mRNA splicing of synaptic genes in mice
SFRS8 is a member of SR family protein. It is also a known splicing factor that is highly expressed in the brain. However, its function in the brain remains elusive. Here, we find that SFRS8 is required to maintain normal synaptic protein levels as well as synaptic densities. Mechanistically, we demonstrate that SFRS8 interacts with SF3B3, a major component of U2 snRNP complex, and regulates the RNA alternative splicing process. Specifically, SFRS8 regulates the levels of PSD95, through enhancing the loading of Psd95 mRNA on the U2 snRNP complex and increasing the skipping of exon18 of Psd95. We further demonstrate that SFRS8 knockdown in the hippocampus leads to reduced synaptic protein expression, decreased spine density, consequently defective memory in mice. Similar reduction in synaptic protein expression and synaptic density are also evident in cultured neurons. Taken together, SFRS8 regulates memory function in mice through altering the alternative splicing and expression of synaptic genes via SFRS8-SF3B3 interaction. Overall design: We conducted RNA sequencing on the hippocampal tissues collected from control and SFRS8 KD mice