Variant BDNF (Val66Met) impact on brain structure and function

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are a unique family of polypeptide growth factors that influence differentiation and survival of neurons in the developing nervous system. In adults, BDNF is important in regulating synaptic plasticity and connectivity in the brain. Recently, a common single-nucleotide polymorphism in the human BDNF gene, resulting in a valine to methionine substitution in the prodomain (Val66Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders. An understanding of how this naturally occurring polymorphism affects behavior, anatomy, and cognition in adults is an important first step in linking genetic alterations in the neurotrophin system to definable biological outcomes in humans. We review the recent literature linking this BDNF polymorphism to cognitive impairment in the context of in vitro and transgenic animal studies that have established BDNF’s central role in neuronal functioning in the adult brain.

[1]  Niraj S. Desai,et al.  BDNF regulates the intrinsic excitability of cortical neurons. , 1999, Learning & memory.

[2]  Nancy Y. Ip,et al.  Potentiation of developing neuromuscular synapses by the neurotrophins NT-3 and BDNF , 1993, Nature.

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

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

[5]  Richard F. Thompson,et al.  Brain-Derived Neurotrophic Factor Plays a Critical Role in Contextual Fear Conditioning , 2004, The Journal of Neuroscience.

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

[7]  D. Collier,et al.  Association of BDNF with anorexia, bulimia and age of onset of weight loss in six European populations. , 2004, Human molecular genetics.

[8]  M. Barrot,et al.  Essential role of brain-derived neurotrophic factor in adult hippocampal function. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  S. Gabriel,et al.  Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus , 2002, Molecular Psychiatry.

[10]  Tobias Bonhoeffer,et al.  Essential Role for TrkB Receptors in Hippocampus-Mediated Learning , 1999, Neuron.

[11]  N. Syed,et al.  Neurotrophic activities of trk receptors conserved over 600 million years of evolution. , 2004, Journal of neurobiology.

[12]  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.

[13]  M. Chao Trophic factors: An evolutionary cul‐de‐sac or door into higher neuronal function? , 2000, Journal of neuroscience research.

[14]  Petti T. Pang,et al.  The yin and yang of neurotrophin action , 2005, Nature Reviews Neuroscience.

[15]  Ted Abel,et al.  Recombinant BDNF Rescues Deficits in Basal Synaptic Transmission and Hippocampal LTP in BDNF Knockout Mice , 1996, Neuron.

[16]  E. Schuman,et al.  Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus , 1995, Science.

[17]  R. Poldrack,et al.  Images of Medial Temporal Lobe Functions in Human Learning and Memory , 1998, Neurobiology of Learning and Memory.

[18]  S. Linnarsson,et al.  Learning Deficit in BDNF Mutant Mice , 1997, The European journal of neuroscience.

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

[20]  E. Kandel,et al.  Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice. , 2000, Learning & memory.

[21]  S. Zeiler,et al.  Development/Plasticity/Repair Brain-Derived Neurotrophic Factor Is Required for the Maintenance of Cortical Dendrites , 2022 .

[22]  G. MacQueen,et al.  Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. , 2001, Behavioral neuroscience.

[23]  B. Zörner,et al.  Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive” , 2003, Biological Psychiatry.

[24]  M. Riva,et al.  Association between the BDNF 196 A/G polymorphism and sporadic Alzheimer's disease , 2002, Molecular Psychiatry.

[25]  Z. Baquet,et al.  Expression of neurotrophin‐3 in the mouse forebrain: Insights from a targeted LacZ reporter , 2000, The Journal of comparative neurology.

[26]  B. Zörner,et al.  Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior. , 2004, Brain research. Molecular brain research.

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

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

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

[30]  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.

[31]  W. Snider,et al.  Functions of the neurotrophins during nervous system development: What the knockouts are teaching us , 1994, Cell.

[32]  Lawrence C. Katz,et al.  Neurotrophins regulate dendritic growth in developing visual cortex , 1995, Neuron.

[33]  Rüdiger Klein,et al.  Long‐term monitoring of hippocampus‐dependent behavior in naturalistic settings: Mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility , 2002, Hippocampus.

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

[35]  Michael Sendtner,et al.  Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches , 2002, Nature Neuroscience.

[36]  R. Nicoll,et al.  The Role of Brain-Derived Neurotrophic Factor Receptors in the Mature Hippocampus: Modulation of Long-Term Potentiation through a Presynaptic Mechanism involving TrkB , 2000, The Journal of Neuroscience.

[37]  J. Gorski,et al.  Early Striatal Dendrite Deficits followed by Neuron Loss with Advanced Age in the Absence of Anterograde Cortical Brain-Derived Neurotrophic Factor , 2004, The Journal of Neuroscience.

[38]  P. Muglia,et al.  The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. , 2002, American journal of human genetics.

[39]  Kenji Hashimoto,et al.  Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: The possibility to explain ethnic mental traits , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

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

[41]  F. Holsboer,et al.  Intact spatial learning and memory in transgenic mice with reduced BDNF , 1997, Neuroreport.

[42]  M. Gratacós,et al.  Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type , 2003, Molecular Psychiatry.

[43]  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.

[44]  I. Black,et al.  Brain-derived neurotrophic factor rapidly enhances synaptic transmission in hippocampal neurons via postsynaptic tyrosine kinase receptors. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Radeke,et al.  Immunocytochemical localization of TrkB in the central nervous system of the adult rat , 1997, The Journal of comparative neurology.

[46]  T Bonhoeffer,et al.  Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Gorski,et al.  Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice , 2003, Neuroscience.

[48]  Margit Burmeister,et al.  A BDNF Coding Variant is Associated with the NEO Personality Inventory Domain Neuroticism, a Risk Factor for Depression , 2003, Neuropsychopharmacology.

[49]  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.

[50]  Ichiro Kanazawa,et al.  Association studies of multiple candidate genes for Parkinson's disease using single nucleotide polymorphisms , 2002, Annals of neurology.

[51]  Daniel L. Schacter,et al.  Remembrance of Things Past , 1999, Science.