Synaptic m1A remodeling in the mPFC promotes fear extinction via Pten regulation

Post-traumatic stress disorder (PTSD) is marked by intrusive fear memories and impaired extinction learning, yet the underlying molecular mechanism at synapses remains elusive. Here, we uncover a previously unrecognized epitranscriptomic mechanism linking RNA modification to adaptive memory. We show that extinction learning increases synaptic TRMT6/TRMT61A levels, driving the redistribution of m¹A toward activity-relevant transcripts. Explicitly, using subcellular fractionation combined with m¹A RIP-seq, we identify a synapse-specific m¹A pattern, distinct from nuclear and whole mPFC profiles, marked by reduced 5’ UTR and enriched coding region and 3’ UTR methylation during extinction learning. Moreover, TRMT61A-mediated m¹A deposition in the 3’ UTR of Pten mRNA within synaptic compartments enhances transcript stability and thereby increases PTEN protein levels. RNA pull-down coupled with mass spectrometry identified SRSF1 as a synapse-enriched, extinction-responsive RNA binding protein (RBP) that specifically binds m¹A and mediates downstream post-transcriptional regulation. Notably, TRMT61A-mediated m¹A modification and its recognition by SRSF1 converge on Pten regulation to drive synaptic remodeling and facilitate extinction memory. Site-specific disrupting Pten m¹A site impairs dendritic structure and blocks extinction retrieval, completing a mechanistic loop from RNA mark to behavior. Our findings highlight m¹A as a dynamic regulator of synaptic plasticity and identify a novel molecular circuit that may be targeted for PTSD therapeutics.