Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mus musculus

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 hallmark features of autism, 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. Overall design: Hippocampal neurons were harvested from E16.5 C57bl/6 mice and cultured in vitro for 10 days. Neurons were then treated with 55 mM KCl and RNA was harvested after 0.5 h or 3 h of KCl treatment. Untreated controls were also harvested. Biological dublicates were sequenced for each condition