Landscape of ribosome-engaged transcript isoforms reveals extensive neuronal-cell-class-specific alternative splicing programs

Nervous system function relies on complex assemblies of distinct neuronal cell typesthat have unique anatomical and functional properties instructed by molecular programs. Alternative splicingis a key mechanism for the expansion of molecular repertoires, and protein spliceisoforms shape neuronalcell surface recognition and function. However, the logic of how alternative splicingprograms are arrayed across neuronal cells typesis poorly understood. We systematically mapped ribosome-associated transcript isoforms in genetically defined neurontypes of the mouse forebrain. Our dataset provides an extensive resource of transcript diversity across major neuronclasses. We find that neuronaltranscript isoform profiles reliably distinguish even closely related classes of pyramidal cellsand inhibitory interneurons in the mouse hippocampus and neocortex. These highly specific alternative splicingprograms selectively control synaptic proteins and intrinsic neuronalproperties. Thus, transcript diversification via alternative splicingis a central mechanism for the functional specificationof neuronal cell typesand circuits. Furlanis, Traunmuller et al. uncover hundreds of alternative splicingevents that distinguish neuronalcell classes. Spliceisoforms primarily encode synaptic and intrinsic neuronalproperties. Data are available online in the SpliceCode database.