Reduced synaptic density is a hallmark cellular phenotype in schizophrenia (SCZ), consistently observed across multiple experimental paradigms. Still, the molecular mechanisms underlying this deficit remain poorly understood. Through transcriptomic analysis of iPSC-derived cortical neurons we identified altered polyadenylation patterns of the 3’UTR in SCZ patients that results in shorter 3’UTRs and, ultimately, disrupted transcript localization. This pattern was enriched in genes involved in synaptic signaling, providing an interesting molecular basis for the observed synaptic deficits. Literature has shown alternative polyadenylation (APA) to be fundamental in neurons, however its contribution to psychiatric disorders remains elusive.
To better understand this link, we selected SHANK3, a gene known to be involved in several psychiatric and neurodevelopmental disorders. Our results highlighted a shift in the intracellular localization of both SHANK3 transcript and protein. Moreover, we showed that the reduced localization of SHANK3 protein in the neurites is associated with an altered synaptic density and altered connectivity of the cells.
To establish causality, we generated SHANK3 long-3'UTR knockout cell lines using CRISPR-Cas9. These cells, expressing only short 3'UTR isoforms, recapitulated the molecular and functional SCZ phenotypes: increased total SHANK3 protein expression but reduced neurite localization and impaired electrophysiology, demonstrating that altered 3'UTR usage alone induces synaptic deficits.
Our findings reveal a novel mechanism where differential APA disrupts subcellular localization of synaptic proteins, contributing to reduced synaptic density in schizophrenia. This establishes a causal link between 3'UTR processing alterations and compromised neuronal connectivity, potentially opening therapeutic avenues targeting mRNA localization or synaptic restoration.