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Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency



Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.

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This work was supported by the Swiss National Science Foundation (Grant No. 310030_146217) and the European Union Seventh Framework Program (FP7/2007–2011) (Grant No. 259679) (to UM), by INSERM (to PC), by ETH Zurich (to WL) and by MINECO (Spain, SAF2013-42445R) (to ES). ACR is the recipient of an Australian Research Council Discovery Early Career Research Award (DE140101071). We are grateful to F Mouttet, E Weber, F Müller, S Giovanoli and S Kaufman for assistance in experimentation or genotyping; M Riva and D Ramachandran for helpful discussions; N Jejelava and M Arnold for advice on surgery; and the animal technician team for contribution to animal husbandry. We thank the National Institute of Mental Health's Chemical Synthesis and Drug Supply Program for providing CNQX, NBQX and D-APV.

Author contributions

MAL designed the study, analyzed data, wrote the original manuscript and performed the behavioral, surgical, metabolic and imaging experiments. OL performed and analyzed the electrophysiology experiments. JR and MAL did the western blots. UW contributed to behavior and surgeries. JI developed the LTD protocol. TN, TG and MAL did the immunostainings. LP and ES generated the transgenic mice and contributed to writing. AR, CL and WL contributed to data interpretation and writing. PC and UM designed and supervised the entire study, analyzed data and wrote the manuscript.

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Correspondence to M A Labouesse, P Chavis or U Meyer.

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The authors declare no conflict of interest.

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Labouesse, M., Lassalle, O., Richetto, J. et al. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. Mol Psychiatry 22, 961–971 (2017).

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