POTENTIATING LSD1 AS AN EMERGING THERAPEUTIC APPROACH TO PRESERVE ADAPTIVE FEAR MEMORY UPDATING

Adaptive updating of fear memories is essential for a flexible behavior, and its impairment contributes to the maladaptive persistence of fear observed in post-traumatic stress disorders. Memory consolidation and reconsolidation rely on activity-dependent gene expression programs that are tightly regulated by epigenetic mechanisms within hippocampal circuits. We previously identified Lysine-Specific Demethylase 1 (LSD1/KDM1A) as an epigenetic corepressor of neuroplastic genes in excitatory neurons. LSD1 activity is dynamically regulated by alternative splicing: inclusion of the neuron-specific exon-E8a attenuates its corepressive function, whereas exon skipping enhances transcriptional repression. In the mouse hippocampus, exposure to stressful experiences transiently reduces E8a inclusion, suggesting an experience-dependent mechanism that modulates epigenetic responses during fear memory consolidation-updating. To test whether targeted modulation of LSD1 splicing influences fear memory plasticity, we combined contextual fear conditioning with ventral hippocampus–restricted delivery of an antisense oligonucleotide (ASO-E8a) that promotes exon E8a skipping and selectively enhances LSD1 function. Increasing LSD1 activity before training in a contextual fear conditioning paradigm and across subsequent memory recall sessions produced a robust reduction in freezing behavior at a later time point, consistent with facilitated adaptive memory updating, whereas control animals showed no change in fear expression. In addition, ASO-E8a elicited anxiolytic-like effects in unstressed animals, supporting a broader role for LSD1-dependent epigenetic regulation in emotional processing.
Ongoing studies aim to define the transcriptional and epigenomic programs controlled by LSD1 during fear memory reconsolidation. Together, these findings support alternative splicing–based modulation of chromatin regulators as a potentially targetable strategy to reshape maladaptive fear memories.