TRANSCRIPTOMIC LANDSCAPE AND ENDOCANNABINOID PROFILE IN A MOUSE MODEL OF POSTPARTUM DEPRESSION

Peripartum depression (PPD) affects up to 20% of women during their reproductive life, compromising maternal well-being and interfering with the mother-infant bond. Following recent findings on brexanolone, a positive allosteric modulator of GABA-A receptors, research has primarily focused on the involvement of the GABAergic system. However, a knowledge gap remains concerning the contributors to the development of this disease. In this regard, the neuromodulator role of the endocannabinoid system (ECS) has been highlighted for its interaction with various neurotransmitter systems and the participation in mood and anxiety regulation, although it has not been thoroughly investigated. This study aims to elucidate the underlying mechanisms of PPD, specifically, endocannabinoid levels and potential transcriptomic changes in emotion processing- and cognition-related brain areas. To do so, we utilized a well-established mouse model of PPD by combining maternal separation and early weaning (MSEW). Their control counterparts were left in a standard nest condition. After assessment of anxiety- and depressive-like behaviors, endocannabinoid levels were measured with LC-MS/MS technique in the hippocampus (HPC). Bulk RNA sequencing was performed to characterize the molecular landscape in the medial prefrontal cortex and HPC. We observed significant alterations in 2-arachidonoyl glycerol levels in MSEW dams, suggesting that endocannabinoid imbalance participates in the pathophysiology of PPD. Moreover, transcriptomic analysis identified widespread dysregulation across multiple gene networks, particularly in memory and learning processes. Taken together, our findings implicate the ECS in PPD pathology and highlight distinct gene signatures, offering new insights into the molecular mechanisms underlying this disorder.