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Control of neuronal synapse specification by a highly dedicated alternative splicing program

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Science  20 May 2016:
Vol. 352, Issue 6288, pp. 982-986
DOI: 10.1126/science.aaf2397

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Synapse identity through specific splicing

What are the mechanisms that create different, highly specific types of synapses? Traunmüller et al. found that the RNA-binding protein SLM2 regulated a very small number of alternative splicing decisions in mouse hippocampal neurons. Disrupting this splicing program resulted in specific defects in transsynaptic protein complexes. Glutamatergic transmission and synaptic plasticity were impaired. Genetically restoring one single alternative splicing event was enough to recover synaptic plasticity. SLM2 thus activates a highly specific alternative splicing program that controls the properties of glutamatergic synapses.

Science, this issue p. 982

Abstract

Alternative RNA splicing represents a central mechanism for expanding the coding power of genomes. Individual RNA-binding proteins can control alternative splicing choices in hundreds of RNA transcripts, thereby tuning amounts and functions of large numbers of cellular proteins. We found that the RNA-binding protein SLM2 is essential for functional specification of glutamatergic synapses in the mouse hippocampus. Genome-wide mapping revealed a markedly selective SLM2-dependent splicing program primarily consisting of only a few target messenger RNAs that encode synaptic proteins. Genetic correction of a single SLM2-dependent target exon in the synaptic recognition molecule neurexin-1 was sufficient to rescue synaptic plasticity and behavioral defects in Slm2 knockout mice. These findings uncover a highly selective alternative splicing program that specifies synaptic properties in the central nervous system.

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