A key challenge in understanding and ultimately treating autism is to identify common molecular mechanisms underlying this genetically heterogeneous disorder. Transcriptomic profiling of autistic brains has revealed correlated misregulation of the neuronal splicing regulator nSR100/SRRM4 and its target microexon splicing program in more than one-third of analyzed individuals. To investigate whether nSR100 misregulation is causally linked to autism, we generated mutant mice with reduced levels of this protein and its target splicing program. Remarkably, these mice display multiple autistic-like features, including altered social behaviors, synaptic density, and signaling. Moreover, increased neuronal activity, which is often associated with autism, results in a rapid decrease in nSR100 and splicing of microexons that significantly overlap those misregulated in autistic brains. Collectively, our results provide evidence that misregulation of an nSR100-dependent splicing network controlled by changes in neuronal activity is causally linked to a substantial fraction of autism cases.

Introduction

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et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Recently, from comparisons of a larger cohort of autistic and control brain samples using a more sensitive RNA-seq analysis pipeline, it was observed that the splicing of 30%–40% of brain-specific microexons is disrupted in over one-third of analyzed idiopathic ASD individuals (). Microexons are a class of highly conserved, predominantly frame-preserving, and neuronal-enriched 3–27 nt cassette exons. They generally reside on protein surfaces, impact protein-protein interactions, and are significantly enriched in genes with critical roles in synaptic biology and with genetic links to ASD (). Most neural microexons are controlled by nSR100, and nSR100 mRNA levels are downregulated in autistic brains that display microexon skipping (). These observations have raised the intriguing possibility that disruption of nSR100 may represent a common mechanism underlying a substantial fraction of ASD cases. However, the mechanism(s) underlying reduced nSR100 expression and misregulation of its target splicing program in autistic brains have not been previously examined, nor has it been determined whether reduced expression of nSR100, or of any other splicing regulator, is causally linked to ASD.