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The role of PPAR-γ in memory deficits induced by prenatal and lactation alcohol exposure in mice

Molecular Psychiatry volume 28, pages 3373–3383 (2023)Cite this article

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Abstract

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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Fig. 1: Alcohol consumption by dams during gestation and lactation.
Fig. 2: Hippocampal alterations in the expanded ECS induced by PLAE.
Fig. 3: Endogenous or exogenous PPAR-γ activation ameliorates memory impairments in PLAE mice.
Fig. 4: PLAE reduces astrocytic PPAR-γ primarily in CA1 of the HPC.
Fig. 5: Astrocytic PPAR-γ upregulation in dorsal HPC rescues memory deficits induced by PLAE.

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Acknowledgements

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.

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  1. Neurobiology of Behavior Research Group (GReNeC-NeuroBio), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Alba Garcia-Baos, Ines Gallego-Landin, Rafael de la Torre & Olga Valverde

  2. Neuroscience Research Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain

    Alba Garcia-Baos, Antoni Pastor, Rafael de la Torre & Olga Valverde

  3. Research Program on Biomedical Informatics (GRIB), IMIM-Hospital del Mar Research Institute, Universitat Pompeu Fabra, Barcelona, Spain

    Ferran Sanz

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AGB and OV were responsible for the study concept and design. AGB and IGL carried out the behavioral experiments (DID test). AGB conducted the pharmacological and genetic manipulations and the posterior behavioral experiments (memory tests), as well as the RT-qPCR and IHC assays. AGB, FS and OV analyzed and interpreted the data. AP and RT carried out the LC-MS/MS studies and analyses. AGB, IGL, AP, and OV drafted the manuscript. All authors critically reviewed the content of the manuscript.

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Correspondence to Olga Valverde.

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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 28, 3373–3383 (2023). https://doi.org/10.1038/s41380-023-02191-z

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