Epigenetics in PTSD: potentiating LSD1 to Rewire Fear Memory Circuits

Post-Traumatic Stress Disorder (PTSD) is characterized by intrusive thoughts and flashbacks triggered by neutral cues, a phenomenon attributed to maladaptive fear generalization. A hallmark of PTSD is indeed the heightened salience of otherwise harmless contextual stimuli, which trigger the retrieval of traumatic memories and contribute to chronic anxiety and impaired emotional regulation. Recent advances have highlighted the process of memory reconsolidation, whereby reactivated memories become temporarily labile and susceptible to modification, particularly within hippocampal circuits. In resilient individuals, reconsolidation supports adaptive memory updating; in PTSD, however, it may abnormally reinforce traumatic content. We previously identified Lysine-Specific Demethylase 1 (LSD1) as an epigenetic co-repressor of neuroplasticity-related genes, including the Immediate Early Genes. In the mammalian brain, LSD1 activity is negatively regulated by the inclusion of exon E8a via alternative splicing, which abrogates its co-repressor function. In the mouse hippocampus, exposure to strong environmental stimuli (e.g., stress or trauma) temporarily reduces E8a inclusion, thereby boosting LSD1 activity as a potential homeostatic mechanism to modulate glutamatergic signaling in high-demand states. To explore the role of LSD1 in PTSD-relevant memory reconsolidation, we used a rodent paradigm of contextual fear conditioning (CFC) combined with an exon E8a skipping pharmacological strategy (ASO-E8a) to selectively promote LSD1 activity in the ventral hippocampus. Preliminary results show that ASO-E8a–treated mice exhibit significantly reduced freezing behavior upon re-exposure to the fear context, compared to controls (ASO-SCRA), suggesting that LSD1 activity may dampen fear memory. In addition, anxiolytic-like effects of ASO-E8a were observed in unstressed animals, indicating a broader role of LSD1 in emotional regulation beyond trauma-related memory. These findings identify LSD1 as a potential novel epigenetic regulator of fear memory updating, supporting its potential as a novel therapeutic target in PTSD and related disorders.