MECHANISM OF HOMER1A EXPRESSION IN NEURONS AND DISRUPTION IN PERSISTENT MTORC1 SIGNALING

Synaptic plasticity relies on well-characterized activity-driven changes in gene expression. However, the mechanisms of neuronal activity-driven changes in alternative splicing and polyadenylation are understudied. Here, we investigate the mechanism of expression for alternative polyadenylation isoform Homer1a, an immediate early gene essential to several forms of synaptic plasticity. We demonstrate that neuronal stimulation depletes U1 snRNP, a critical splice factor, from Homer1 pre-mRNA and that this depletion is sufficient for Homer1a expression. Because U1 snRNP binds ubiquitously, we tested the generality of activity-driven U1 snRNP depletion with RNA immunoprecipitation sequencing, which revealed that neuronal activity significantly changes U1 snRNP binding to ~2000 transcripts. For a subset of transcripts, the change in U1 snRNP binding is accompanied by a change in intronic polyadenylation site use, as is the case for Homer1a. This subset is enriched for transcripts encoding synaptic proteins involved in the control of excitability. Additionally, this subset is enriched for transcripts containing the binding motif of Sam68, a known neuronal alternative polyadenylation factor that may be working with U1 snRNP. Results demonstrate that activity-driven changes in alternative polyadenylation within introns are more widespread than previously thought and may serve an important role in synaptic signaling and structure. Further, Homer1a expression is disrupted in mouse Alzheimer’s Disease (AD) models and other models with persistently increased mTORC1 signaling. Homer1a is critical for synaptic plasticity and memory consolidation, and so its disrupted expression in human AD brain could rationally contribute to cognitive failure in AD. Here, we present our findings that increased mTORC1 signaling interrupts the activity-dependent U1 snRNP mechanism to cause disrupted Homer1a expression