Potentiating LSD1 as an emerging therapeutic approach to preserve adaptive fear memory updating

Adaptive updating of fear memories is essential for flexible behavior, and its impairment contributes to the maladaptive persistence of fear observed in stress-related disorders such as post-traumatic stress disorder (PTSD). Memory formation 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 co-repressor of neuroplasticity-related genes, including immediate early genes. In neurons, LSD1 activity is dynamically regulated by alternative splicing: inclusion of the neuron-specific exon E8a attenuates its repressive function, whereas exon skipping enhances chromatin repression. In the mouse hippocampus, exposure to salient or stressful experiences transiently reduces E8a inclusion, suggesting an experience-dependent mechanism that modulates epigenetic responses during memory updating. To test whether targeted modulation of LSD1 splicing influences fear memory plasticity, we combined contextual fear conditioning with a region-specific antisense oligonucleotide strategy (ASO-E8a) to promote exon E8a skipping and selectively potentiate LSD1 activity in the ventral hippocampus. Enhancing LSD1 activity during memory reactivation resulted in a significant reduction of freezing behavior, consistent with facilitated adaptive memory updating, whereas control animals showed no change in fear expression. Additionally, ASO-E8a treatment produced anxiolytic-like effects in unstressed animals, indicating 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 mechanistically precise and potentially targetable strategy to reshape maladaptive fear memories.