title: Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency.
abstract: 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.
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: M A
authors.initials: MA
authors.lastname: Labouesse
authors.affiliation: INSERM, INMED UMR S 901, Aix-Marseille Université, Marseille, France.
authors.forename: O
authors.initials: O
authors.lastname: Lassalle
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Richetto
authors.affiliation: INSERM, INMED UMR S 901, Aix-Marseille Université, Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Iafrati
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Weber-Stadlbauer
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Notter
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Gschwind
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Vall [Dacute ]Hebron Institut de Recerca (VHIR), Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Pujadas
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain.|Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Vall [Dacute ]Hebron Institut de Recerca (VHIR), Barcelona, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA Academia), Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Soriano
authors.affiliation: School of Health and Biomedical Sciences, RMIT, Melbourne, VIC, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Reichelt
authors.affiliation: Laboratory of Cell Biophysics, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland.|Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
authors.forename: C
authors.initials: C
authors.lastname: Labouesse
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: W
authors.initials: W
authors.lastname: Langhans
authors.affiliation: INSERM, INMED UMR S 901, Aix-Marseille Université, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Chavis
authors.affiliation: Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.|Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.|Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Meyer
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D008297:Male; D044342:Malnutrition / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity; D017397:Prefrontal Cortex / Q000254:growth & development* / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D000091042:Reelin Protein; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases