Impact of the BDNF Val66Met Polymorphism on Cognition

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family and is implicated as a modulator of neuronal survival and differentiation, synaptic plasticity, and higher order cognitive functions such as learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of learning in humans. To better understand the impact of this SNP on biological function, the authors generated a mouse model containing the BDNF Met allele, which they found to replicate the key phenotypes observed in humans and provided further insight into the functional impact of this SNP in vivo. They used a “bottom-up” approach to study the BDNF SNP, which provided external validation in biologically less complex, genetically uniform systems, which minimized the variability inherent in human studies. In this review, the authors discuss the impact of the BDNF SNP on learning and memory while providing arguments for the relevance of a vertically integrated approach to studying human genetic variants.

[1]  K. Ressler,et al.  Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder , 2012, Trends in Neurosciences.

[2]  Paresh D Patel,et al.  Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons , 2004, The Journal of Neuroscience.

[3]  H. Scharfman,et al.  Brain-derived neurotrophic factor. , 2004, Growth factors.

[4]  C. Beste,et al.  The functional BDNF Val66Met polymorphism affects functions of pre-attentive visual sensory memory processes , 2011, Neuropharmacology.

[5]  Kiyotaka Nemoto,et al.  Dose-dependent effect of the Val66Met polymorphism of the brain-derived neurotrophic factor gene on memory-related hippocampal activity , 2008, Neuroscience Research.

[6]  J. Hauser,et al.  Polymorphism of the brain-derived neurotrophic factor gene and performance on a cognitive prefrontal test in bipolar patients. , 2003, Bipolar disorders.

[7]  J. Hauser,et al.  Illness-specific association of val66met BDNF polymorphism with performance on Wisconsin Card Sorting Test in bipolar mood disorder , 2006, Molecular Psychiatry.

[8]  L. Minichiello.  TrkB signalling pathways in LTP and learning , 2009, Nature Reviews Neuroscience.

[9]  F. Lee,et al.  Neurotrophin signalling in health and disease. , 2006, Clinical science.

[10]  Bai Lu,et al.  Pro-Region of Neurotrophins Role in Synaptic Modulation , 2003, Neuron.

[11]  M. Chao,et al.  Neurotrophins and their receptors: A convergence point for many signalling pathways , 2003, Nature Reviews Neuroscience.

[12]  J. Groves,et al.  Is it time to reassess the BDNF hypothesis of depression? , 2007, Molecular Psychiatry.

[13]  S. Tsai,et al.  Association Study of a Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism and Personality Trait and Intelligence in Healthy Young Females , 2004, Neuropsychobiology.

[14]  T. Wassink,et al.  Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. , 2006, Archives of general psychiatry.

[15]  T. Bliss,et al.  The Role of Extracellular Regulated Kinases I/II in Late-Phase Long-Term Potentiation , 2002, The Journal of Neuroscience.

[16]  C. Siao,et al.  Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior , 2006, Science.

[17]  Heidi M. Schambra,et al.  Direct Current Stimulation Promotes BDNF-Dependent Synaptic Plasticity: Potential Implications for Motor Learning , 2010, Neuron.

[18]  Mu-ming Poo,et al.  Neurotrophins as synaptic modulators , 2001, Nature Reviews Neuroscience.

[19]  J. Morris,et al.  BDNF polymorphism rs6265 and hippocampal structure and memory performance in healthy control subjects , 2010, Psychiatry Research.

[20]  Philippe P Roux,et al.  Neurotrophin signaling through the p75 neurotrophin receptor , 2002, Progress in Neurobiology.

[21]  C. Bramham,et al.  BDNF function in adult synaptic plasticity: The synaptic consolidation hypothesis , 2005, Progress in Neurobiology.

[22]  S. Cramer,et al.  Intense training overcomes effects of the val66met BDNF polymorphism on short-term plasticity , 2011, Experimental Brain Research.

[23]  A. Meyer-Lindenberg,et al.  The Brain-derived Neurotrophic Factor Val66met Polymorphism and Variation in Human Cortical Morphology , 2022 .

[24]  M. Greenberg,et al.  New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function , 2009, The Journal of Neuroscience.

[25]  D Robinson,et al.  Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation , 2005, Molecular Psychiatry.

[26]  E. Shooter,et al.  Two conserved domains in the NGF propeptide are necessary and sufficient for the biosynthesis of correctly processed and biologically active NGF. , 1991, The EMBO journal.

[27]  C. Marshall,et al.  Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells , 1994, Cell.

[28]  Bai Lu,et al.  BDNF and activity-dependent synaptic modulation. , 2003, Learning & memory.

[29]  P. Rodríguez,et al.  BDNF val66met polymorphism influences motor system function in the human brain. , 2010, Cerebral cortex.

[30]  Roberto Cabeza,et al.  Brain‐derived neurotrophic factor val66met polymorphism and hippocampal activation during episodic encoding and retrieval tasks , 2010, Hippocampus.

[31]  B. Casey,et al.  Variant brain‐derived neurotrophic factor Val66Met endophenotypes: implications for posttraumatic stress disorder , 2010, Annals of the New York Academy of Sciences.

[32]  K. Bath,et al.  Variant BDNF Val66Met Polymorphism Affects Extinction of Conditioned Aversive Memory , 2009, The Journal of Neuroscience.

[33]  Carol Dobson-Stone,et al.  Disturbances in selective information processing associated with the BDNF Val66Met polymorphism: Evidence from cognition, the P300 and fronto-hippocampal systems , 2009, Biological Psychology.

[34]  David P Wolfer,et al.  Knockout of ERK1 MAP Kinase Enhances Synaptic Plasticity in the Striatum and Facilitates Striatal-Mediated Learning and Memory , 2002, Neuron.

[35]  Johannes Kornhuber,et al.  Influence of brain-derived neurotrophic-factor and apolipoprotein E genetic variants on hippocampal volume and memory performance in healthy young adults , 2011, Journal of Neural Transmission.

[36]  R. Straub,et al.  BDNF Val66Met polymorphism significantly affects d′ in verbal recognition memory at short and long delays , 2008, Biological Psychology.

[37]  B. Franke,et al.  Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: effects of gender and ethnicity , 2010, Molecular Psychiatry.

[38]  Barbara L. Hempstead,et al.  Regulation of Cell Survival by Secreted Proneurotrophins , 2001, Science.

[39]  Muriel Walshe,et al.  Association between BDNF val66 met genotype and episodic memory , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[40]  T. Robbins,et al.  The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease , 2005, Journal of Neurology.

[41]  B. McEwen,et al.  Impact of genetic variant BDNF (Val66Met) on brain structure and function. , 2008, Novartis Foundation symposium.

[42]  D. G. Herrera,et al.  Sortilin Controls Intracellular Sorting of Brain-Derived Neurotrophic Factor to the Regulated Secretory Pathway , 2005, The Journal of Neuroscience.

[43]  M. Egan,et al.  Brain-Derived Neurotrophic Factor val66met Polymorphism Affects Human Memory-Related Hippocampal Activity and Predicts Memory Performance , 2003, The Journal of Neuroscience.

[44]  J. Baraban,et al.  Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation , 2009, Proceedings of the National Academy of Sciences.

[45]  K. Christian,et al.  BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? , 2008, Neurobiology of Learning and Memory.

[46]  Joanna Hauser,et al.  Prefrontal cognition in schizophrenia and bipolar illness in relation to Val66Met polymorphism of the brain‐derived neurotrophic factor gene , 2006, Psychiatry and clinical neurosciences.

[47]  Y. Loh,et al.  Sorting and Activity-Dependent Secretion of BDNF Require Interaction of a Specific Motif with the Sorting Receptor Carboxypeptidase E , 2005, Neuron.

[48]  Barbara L. Hempstead,et al.  ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of p75NTR and Sortilin , 2005, The Journal of Neuroscience.

[49]  S. Cramer,et al.  BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex , 2006, Nature Neuroscience.

[50]  Pingyuan Gong,et al.  Effect of BDNF Val66Met Polymorphism on Digital Working Memory and Spatial Localization in a Healthy Chinese Han Population , 2009, Journal of Molecular Neuroscience.

[51]  E. Huang,et al.  Neurotrophins: roles in neuronal development and function. , 2001, Annual review of neuroscience.

[52]  P Rabbitt,et al.  Brain‐derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly , 2008, Genes, brain, and behavior.

[53]  M. Egan,et al.  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function , 2003, Cell.

[54]  E. Beghi,et al.  BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson’s disease , 2009, European journal of neurology.

[55]  G. Glover,et al.  A Genetic Variant BDNF Polymorphism Alters Extinction Learning in Both Mouse and Human , 2010, Science.