Potentiating LSD1 via ASO-mediated exon skipping: an epigenetic approach to study fear memory

Memory formation and updating rely on dynamic molecular processes, including synaptic plasticity and activity-dependent gene expression. These processes are further regulated by epigenetic mechanisms, which modulate transcriptional programs in response to neuronal activity, especially within hippocampal circuits. During memory reactivation, memories enter a transient labile phase, allowing them to be strengthened or weakened. Dysregulation of such memory-updating mechanisms can lead to maladaptive persistence of fear, as observed in stress-related disorders such as Post-Traumatic Stress Disorder (PTSD), where neutral cues aberrantly trigger traumatic memory retrieval. 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 function is dynamically regulated by alternative splicing: inclusion of the neuron-specific exon E8a inhibits its co-repressor activity, whereas exon skipping enhances epigenetic repression. In the mouse hippocampus, exposure to salient or stressful stimuli transiently reduces E8a inclusion, suggesting an experience-dependent epigenetic mechanism that tunes transcriptional responses during high-demand states. To investigate the role of LSD1 splicing regulation in fear memory updating, we employed a contextual fear conditioning paradigm combined with an antisense oligonucleotide strategy (ASO-E8a) to promote exon E8a skipping and selectively enhance LSD1 activity in the ventral hippocampus. Enhancing LSD1 activity via ASO-E8a resulted in a robust reduction of freezing behavior upon memory reactivation, consistent with adaptive memory-update process. In control animals we observed no reduction in fear expression. In addition, anxiolytic-like effects were observed in unstressed animals, indicating a broader involvement of LSD1-dependent regulation in emotional processing. Ongoing studies aim to define the transcriptional and epigenomic programs regulated by LSD1 during memory reconsolidation. Together, these findings highlight alternative splicing–dependent modulation of chromatin regulators as a potential mechanism underlying fear memory plasticity and stress-related psychopathology.