Figure 9. Model linking electrical activity with Nova-dependent splicing of cryptic NMD exons to maintain the balance of synaptic proteins.
In WT brain, NOVA represses some cryptic NMD isoforms (small red diamonds on left) while promoting others (large red pentagons on right), thereby maintaining the balance of protein levels. To a lesser degree, NOVA also stabilizes transcripts through 3′ UTR interactions (Figure 8). In DKO brain, the absence of NOVA disturbs this balance of protein in expression, contributing to aberrations in synaptic transmission. For example, Nova-regulation of cryptic NMD exons alters levels of the NMDA-receptor associated Dlg3 (Figures 2 and 3) and sodium channel Scn9a (Figure 4) proteins, which are implicated in familial epileptic disorders and are dynamically regulated after seizures in mice (Figure 6).