Patients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates underlying these deficits remain unclear. Here, we show that prenatal and lactation alcohol exposure (PLAE) in mice induces FASD-like memory impairments. This is accompanied by a reduction of N-acylethanolamines (NAEs) and peroxisome proliferator-activated receptor gamma (PPAR-γ) in the hippocampus specifically in a childhood-like period (at post-natal day (PD) 25). To determine their role in memory deficits, two pharmacological approaches were performed during this specific period of early life. Thus, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase NAEs, with GW9662, a PPAR-γ antagonist; ii) pioglitazone, a PPAR-γ agonist. We observed that URB597 suppresses PLAE-induced memory deficits through a PPAR-γ dependent mechanism, since its effects are prevented by GW9662. Direct PPAR-γ activation, using pioglitazone, also ameliorates memory impairments. Lastly, to further investigate the region and cellular specificity, we demonstrate that an early overexpression of PPAR-γ, by means of a viral vector, in hippocampal astrocytes mitigates memory deficits induced by PLAE. Together, our data reveal that disruptions of PPAR-γ signaling during neurodevelopment contribute to PLAE-induced memory dysfunction. In turn, PPAR-γ activation during a childhood-like period is a promising therapeutic approach for memory deficits in the context of early alcohol exposure. Thus, these findings contribute to the gaining insight into the mechanisms that might underlie memory impairments in FASD patients.
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This work was supported by the Ministerio de Economia y Competitividad (#PID2019-104077RB-100 - MCIN/AEI/10.13039/501100011033), Ministerio de Sanidad (Plan Nacional sobre Drogas #2018/007 and ISCIII-Feder-RIAPAd-RICORS #RD21/0009/001) by the EU NextGeneration and by the Generalitat de Catalunya, AGAUR (#2021SGR00485). AG-B received a FI-AGAUR grant from the Generalitat de Catalunya (#2019FI_B0081). IG-L obtained a grant from the Ministerio de Ciencia e Innovación (#PRE2020-091923) The Department of Medicine and Health Sciences (UPF) is a “Unidad de Excelencia María de Maeztu” funded by the AEI (#CEX2018-000792-M). OV is recipient of an ICREA Academia Award (Institució Catalana de Recerca i Estudis Avançats, Generalitat de Catalunya). The authors wish to thank Xavier Puig-Reyne for the technical support.
The authors declare no competing interests.
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Garcia-Baos, A., Pastor, A., Gallego-Landin, I. et al. The role of PPAR-γ in memory deficits induced by prenatal and lactation alcohol exposure in mice. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02191-z