Epigenetic Control of Anxiety through LSD1 Splice Switching

Anxiety emerges when neural circuits lose the ability to flexibly update internal models of the environment, leading to threat-biased prediction and behavioral inhibition. How this loss of flexibility is regulated at the neuronal epigenome remains poorly understood. Here we identify alternative splicing of the epigenetic chromatin regulator lysine-specific demethylase 1 (LSD1/KDM1A) as a key mechanism controlling anxiety-related states in the mouse ventral hippocampus. The ubiquitously expressed isoform ubLSD1 represses transcriptional programs instrumental to glutamatergic synaptic potentiation, an activity antagonized by inclusion of the neuron-specific exon E8a. Genetic removal of E8a produces a robust anxiolytic phenotype, defining reduced E8a inclusion as a protective synaptic configuration. Consistently, E8a splicing is transiently downregulated by acute psychosocial stress through calcium- and NMDA receptor–dependent signaling, indicating that this mechanism is physiologically engaged during anxiogenic experiences. Reduced E8a inclusion constrains CA1excitability, promotes juvenile-like spine states, lowers the AMPA/NMDA ratio, and selectively limits long-term potentiation while sparing long-term depression. Importantly, persistence of this splice response during chronic stress selectively marks resilient individuals, whereas its failure predicts vulnerability. To establish causality, we developed a stereotaxic antisense exon-skipping strategy (ASO-E8a) targeting ventral CA1. Mimicking the physiological stress-induced reduction of E8a inclusion, ASO-E8a induces a potent anxiolytic shift already under basal conditions. Together, these findings identify LSD1 alternative splicing as a state-setting epigenetic mechanism that dynamically limits anxiety and preserves predictive flexibility, defining an unprecedented epigenetic approach to anxiolysis in molecular psychiatry.