Effects of fast-acting antidepressant drugs on a postpartum depression mice model

Postpartum depression (PPD) is a severe psychiatric disorder with devastating consequences on child development and mother's health. Dysregulation of glutamatergic and GABAergic signalling has been described in the corticolimbic system of PPD patients, who also show a downregulation of allopregnanolone levels in serum. Consequently, a synthetic allopregnanolone-based treatment is the current eligible drug to treat PPD patients. Alternatively, ketamine appears to be a promising medication for preventing PPD, nevertheless the differences in efficacy between both treatments remains unknown due to the lack of comparative studies. On this basis, the present study aims to compare the effectiveness of allopregnanolone and ketamine on a PPD-like mouse model. Our results show that postpartum females undergoing a maternal separation with early weaning (MSEW) protocol show increased despair-like behaviour, anhedonia and disrupted maternal care. Such symptoms are accompanied by lower allopregnanolone serum levels, reduction of vesicular transporters of GABA (VGAT) and glutamate (VGLUT1) in the infralimbic cortex (IL), as well as decreased hippocampal cellular proliferation. Furthermore, both drugs prevent despair-like behaviour while only ketamine reverts anhedonia. Both treatments increase hippocampal neurogenesis, while only allopregnanolone raises VGAT and VGLUT1 markers in IL. These findings suggest that ketamine might be even more effective than allopregnanolone, which points out the necessity of including ketamine in clinical studies for PPD patients. Altogether, we propose a new mice model that recapitulates the core symptomatology and molecular alterations shown in PPD patients, which allows us to further investigate both the neurobiology of PPD and the therapeutic potential of antidepressant drugs.This work was supported by Ministerio de Ciencia e Innovación (grants number PID2019-104077-RB-100/AEI/10.13039/501100011033), Ministerio de Sanidad, Asuntos Sociales e Igualdad (Retic-ISCIII-RD/16/0017/0010-FEDER; RICORS, grant number RD21/0009/0001), and Plan Nacional Sobre Drogas (#2018/007) to O.V. A.G-B received a FI-AGAUR grant from the Generalitat de Catalunya (2019FI_B0081) and I.G-L. obtained a grant from the Ministerio de Ciencia e Innovación (PRE2020-091923). The Department of Medicine and Life Sciences (MELIS-UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (CEX2018-000792-M). O.V. is recipient of an ICREA Academia Award (Institució Catalana de Recerca i Estudis Avançats, Generalitat de Catalunya). The authors are indebted to Javier Valle-García (Proteomics and Protein Chemistry Group; Universitat Pompeu Fabra) and Marc González-Colell (Synthetic Biology for Medical Application, Universitat Pompeu Fabra)