Figure 4. Alternative splicing regulation of synaptogenesis and synaptic function.

a |At the presynaptic terminal, alternative splicing of synaptosomal-associated protein 25 (Snap25) by RNA-binding protein fox 1 homologue 1 (RBFOX1) and of the calcium-activated potassium channel subunit alpha 1 (Kcnma1) by muscleblind-like 2 (MBNL2) are important to control neurotransmitter release. Differential splicing of the presynaptic neurexins (Nrxns) at AS4 by KHDRBS proteins (SAM68, SLM1 and SLM2) controls targeting to postsynaptic partners. At excitatory synapses, alternative splicing of the transcript encoding the NMDA receptor subunit GluN1, Grin1, is regulated by RBFOX1 and MBNL2, whereas the polypyrimidine tract binding proteins (PTBPs) control productive splicing of the scaffold protein, postsynaptic density protein 95 (Psd95). Splicing of the transcripts encoding L-type voltage-gated calcium channels, such as the pore-forming subunit Ca_v1.3 (encoded by Cacna1d), by MBNL2 may allow the voltage sensitivity, conductance, or other properties to be tuned as synapses differentiate. At inhibitory synapses, neuro-oncological ventral antigen 2 (NOVA2) mediates alternative splicing of the transcripts encoding many postsynaptic components such as the metabotropic GABA_B receptor (Gabbr2), the inwardly rectifying potassium channel Kir3.2 (Girk2) and the glycine receptor alpha 2 (Glra2). Splicing of the GABA_A receptor subunit transcript (Gabrg2) is controlled by multiple splicing regulators including NOVA2, RBFOX1 and PTBP2. b | Alternative splicing controls the expression and function of many synaptic components. Expression of PSD95 is repressed by PTBP-controlled exclusion of exon 18 until late in neuronal maturation when it is required for synaptogenesis. The gene encoding the voltage-gated sodium channel Na_v1.6, Scn8a, has multiple alternative exons (such as 5N, 5A, 18N and 18A as shown in the figure) that can change its gating properties, determine its localization or alter its overall function. GABA_AR, GABA_A receptor; GABA_BR, GABA_B receptor; GlyR, glycine receptor; NMD, nonsense-mediated decay; NMDAR, NMDA receptor; SAM68, SRC-associated in mitosis 68 kDa protein. Figure adapted from REF. 1, Nature Publishing Group.