A salmi feedback pathway controls cortical network activity and mouse behavior

The brain is made up of trillions of synaptic connec- tions that together form neural networks needed for normal brain function and behavior. SLM2 is a mem- ber of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neu- ral network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feed- back control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse func- tion. Cortical neural network activity dependent on synaptic connections between SLM2-expressing- pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeo- static auto-regulation controlling brain network ac- tivity and behavior.