Neuronal activity-regulated alternative mRNA splicing.

Activity-regulated gene transcription underlies plasticity-dependent changes in the molecular composition and structure of neurons. Numerous genes whose expression is induced by different neuronal plasticity inducing pathways have been identified, but the alteration of gene expression levels represents only part of the complexity of the activity-regulated transcriptional program. Alternative splicing of precursor mRNA is an additional mechanism that modulates the activity-dependent transcriptional signature. Recently developed splicing sensitive transcriptome wide analyses improve our understanding of the underlying mechanisms and demonstrate to what extend the activity regulated transcriptome is alternatively spliced. So far, only for a small group of differentially spliced mRNAs of synaptic proteins, the functional implications have been studied in detail. These include examples in which differential exon usage can result in the expression of alternative proteins which interfere with or alter the function of preexisting proteins and cause a dominant negative functional block of constitutively expressed variants. Such altered proteins contribute to the structural and functional reorganization of pre- and postsynaptic terminals and to the maintenance and formation of synapses. In addition, activity-induced alternative splicing can affect the untranslated regions (UTRs) and generates mRNAs harboring different cis-regulatory elements. Such differential UTRs can influence mRNA stability, translation, and can change the targeting of mRNAs to subcellular compartments. Here, we summarize different categories of alternative splicing which are thought to contribute to synaptic remodeling, give an overview of activity-regulated alternatively spliced mRNAs of synaptic proteins that impact synaptic functions, and discuss splicing factors and epigenetic modifications as regulatory determinants.