A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior

Cell Rep. 2016 Dec 20;17(12):3269-3280. doi: 10.1016/j.celrep.2016.12.002.

Abstract

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback 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 function. 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 homeostatic auto-regulation controlling brain network activity and behavior.

Keywords: Neurexin splicing; RNA binding proteins; RNA-seq; alternative splicing; brain; gene expression; hippocampus; neuron; transcriptome.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alternative Splicing / genetics*
  • Animals
  • Behavior, Animal / physiology
  • Calcium-Binding Proteins
  • Homeostasis / genetics
  • Mice
  • Mice, Knockout
  • Nerve Net*
  • Neural Cell Adhesion Molecules / genetics
  • Pyramidal Cells / metabolism*
  • RNA Precursors / genetics
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Synapses / genetics*
  • Synapses / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Calcium-Binding Proteins
  • Khdrbs1 protein, mouse
  • Khdrbs2 protein, mouse
  • Khdrbs3 protein, mouse
  • Neural Cell Adhesion Molecules
  • Nrxn1 protein, mouse
  • RNA Precursors
  • RNA-Binding Proteins