PMID- 22435671 OWN - NLM STAT- MEDLINE DCOM- 20121120 LR - 20191210 IS - 1601-183X (Electronic) IS - 1601-183X (Linking) VI - 11 IP - 5 DP - 2012 Jul TI - Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits. PG - 513-23 LID - 10.1111/j.1601-183X.2012.00784.x [doi] AB - Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype. CI - (c) 2012 The Authors. Genes, Brain and Behavior (c) 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society. FAU - Uutela, M AU - Uutela M AD - Institute of Biomedicine, Physiology, University of Helsinki, Finland. FAU - Lindholm, J AU - Lindholm J FAU - Louhivuori, V AU - Louhivuori V FAU - Wei, H AU - Wei H FAU - Louhivuori, L M AU - Louhivuori LM FAU - Pertovaara, A AU - Pertovaara A FAU - Akerman, K AU - Akerman K FAU - Castren, E AU - Castren E FAU - Castren, M L AU - Castren ML LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120411 PL - England TA - Genes Brain Behav JT - Genes, brain, and behavior JID - 101129617 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Fmr1 protein, mouse) RN - 139135-51-6 (Fragile X Mental Retardation Protein) SB - IM MH - Animals MH - Behavior, Animal MH - Brain-Derived Neurotrophic Factor/*genetics/metabolism MH - Cells, Cultured MH - Cognition Disorders/*genetics/metabolism MH - Conditioning, Psychological/physiology MH - Fear/physiology MH - Fragile X Mental Retardation Protein/*genetics/metabolism MH - Gait Disorders, Neurologic/*genetics/metabolism MH - Hippocampus/metabolism MH - Hyperkinesis/*genetics/metabolism MH - Maze Learning/physiology MH - Mice MH - Mice, Knockout MH - Motor Activity/genetics MH - Neural Stem Cells MH - Neurons/metabolism MH - Reflex, Startle/genetics EDAT- 2012/03/23 06:00 MHDA- 2012/12/10 06:00 CRDT- 2012/03/23 06:00 PHST- 2012/03/23 06:00 [entrez] PHST- 2012/03/23 06:00 [pubmed] PHST- 2012/12/10 06:00 [medline] AID - 10.1111/j.1601-183X.2012.00784.x [doi] PST - ppublish SO - Genes Brain Behav. 2012 Jul;11(5):513-23. doi: 10.1111/j.1601-183X.2012.00784.x. Epub 2012 Apr 11.