Early Exposure to a High-Fat Diet Impacts on Hippocampal Plasticity: Implication of Microglia-Derived Exosome-like Extracellular Vesicles

Abstract

Adolescence is a transitional period from childhood to adulthood characterized by puberty and brain maturation involving behavioral changes and environmental vulnerability. Diet is one of the factors affecting brain health, potentially leading to long-lasting effects. Hence, we studied the impact of early exposure (P21-60) to a high-fat diet (HFD) on mouse hippocampus, analyzing inflammation, adult neurogenesis, dendritic spine plasticity, and spatial memory. Glycemia and seric pro-inflammatory IL1β were higher in HFD mice without differences on body weight. In the HFD hippocampus, neuroinflammation was evidenced by Iba1+ cells reactivity together with a higher expression of TNFα and IL1β while the neurogenic capability in the dentate gyrus was strongly reduced. We found a predominance of immature Dil-labeled dendritic spines from CA1 neurons along with diminished levels of the scaffold protein Shank2, suggesting a defective connectivity. Moreover, the HFD group exhibited spatial memory alterations. To elucidate whether microglia could be mediating HFD-associated neuronal changes, the lipotoxic context was emulated by incubating primary microglia with palmitate, a saturated fatty acid present in HFD. Palmitate induced a pro-inflammatory profile as shown by secreted cytokine levels. The isolated exosome fraction from palmitate-stimulated microglia induced an immature dendritic spine phenotype in primary GFP+ hippocampal neurons, in line with the in vivo findings. These results provide novel data concerning microglia to neuron communication and highlight that fat excess during a short and early period of life could negatively impact on cognition and synaptic plasticity in a neuroinflammatory context, where microglia-derived exosomes could be implicated.

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Acknowledgements

The authors thank our institutions, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Biología y Medicina Experimental (IBYME), and the National Research Council (CONICET), for the invaluable academic and scientific support. In addition, the authors deeply thank the Williams Foundation for their support and also Soledad Rossi and Monica Frungieri for their kind collaboration and RT PCR expertise, Monica Kotler and team for BV2 cells and advices, Maria Luisa Malosio for help in palmitate preparation setting, and Chiara Elia for EVs isolation expertise and her kind collaboration. We want to especially thank the personnel of the animal facility at IBYME for their help with animal care. This work was funded by Grants to JB PICT 2016-1572 and Roemmers Foundation and to FS PICT 2014-1168 2016-1046 from ANPCyT and PIP from CONICET and was also supported by Cariplo 2015–0594 and Fondazione Pisa to MM. AV was a recipient of a BecAr, Argentina fellowship, to spend 6 months in Milan, Italy, in Matteoli’s laboratory. AV is a postdoctoral fellow from CONICET; GC, MMB, VLL, MEM. JB, and FS are career investigators from CONICET. CP is a doctoral fellow from CONICET. AG and JP are doctoral fellows from ANPCyT.

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Correspondence to Flavia Saravia.

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All animal experiments followed the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Ethical Committee of the Institute of Biology and Experimental Medicine.

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The authors declare that they have no competing interests.

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Vinuesa, A., Bentivegna, M., Calfa, G. et al. Early Exposure to a High-Fat Diet Impacts on Hippocampal Plasticity: Implication of Microglia-Derived Exosome-like Extracellular Vesicles. Mol Neurobiol 56, 5075–5094 (2019). https://doi.org/10.1007/s12035-018-1435-8

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Keywords

  • Hippocampus
  • Dendritic spines
  • High-fat diet
  • Microglia
  • Exosomes
  • Adolescence