title: Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice.
abstract: Several studies have shown that exercise improves cognitive functions and emotional behaviors. Positive effects of exercise have been associated with enhanced brain plasticity, adult hippocampal neurogenesis, and increased levels of brain-derived neurotrophic factor (BDNF). However, a substantial variability of individual response to exercise has been described, which may be accounted for by individual genetic variants. Here, we have assessed whether and how the common human BDNF Val66Met polymorphism influences the neurobiological effects modulated by exercise in BDNF Val66Met knock-in male mice. Wild-type (BDNFVal/Val) and homozygous BDNF Val66Met (BDNFMet/Met) male mice were housed in cages equipped with or without running wheels for 4 weeks. Changes in behavioral phenotype, hippocampal adult neurogenesis, and gene expression were evaluated in exercised and sedentary control mice. We found that exercise reduced the latency to feed in the novelty suppressed feeding and the immobility time in the forced swimming test in BDNFVal/Valbut not in BDNFMet/Metmice. Hippocampal neurogenesis was reduced in BDNFMet/Metmice compared with BDNFVal/Valmice. BDNFMet/Metmice had lower basal BDNF protein levels in the hippocampus, which was not recovered following exercise. Moreover, exercise-induced expression of total BDNF, BDNF splice variants 1, 2, 4, 6 and fibronectin type III domain-containing protein 5 (FNDC5) mRNA levels were absent or reduced in the dentate gyrus of BDNFMet/Metmice. Exercise failed to enhance PGC-1α and FNDC5 mRNA levels in the BDNFMet/Metmuscle. Overall these results indicate that, in adult male mice, the BDNF Val66Met polymorphism impairs the beneficial behavioral and neuroplasticity effects induced by physical exercise.
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, Università di Milano, Milano, Italy.
authors.forename: Alessandro
authors.identifier: 0000-0001-6737-7695
authors.initials: A
authors.lastname: Ieraci
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, Università di Milano, Milano, Italy.
authors.forename: Alessandro I
authors.initials: AI
authors.lastname: Madaio
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, Università di Milano, Milano, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mallei
authors.affiliation: Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.affiliation: Laboratory of Neuropsychopharmacology and Functional Neurogenomics, Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, Università di Milano, Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Popoli
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D006801:Humans; D008297:Male; D001523:Mental Disorders / Q000235:genetics; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D013550:Swimming / Q000502:physiology; D014633:Valine / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C571428:FNDC5 protein, mouse; D005353:Fibronectins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C579455:BDNF protein, human; D008715:Methionine; D014633:Valine