BDNF and Schizophrenia: From Neurodevelopment to Neuronal Plasticity, Learning, and Memory

Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that has been related not only to neurodevelopment and neuroprotection, but also to synapse regulation, learning, and memory. Research focused on the neurobiology of schizophrenia has emphasized the relevance of neurodevelopmental and neurotoxicity-related elements in the pathogenesis of this disease. Research focused on the clinical features of schizophrenia in the past decades has emphasized the relevance of cognitive deficits of this illness, considered a core manifestation and an important predictor for functional outcome. Variations in neurotrophins such as BDNF may have a role as part of the molecular mechanisms underlying these processes, from the neurodevelopmental alterations to the molecular mechanisms of cognitive dysfunction in schizophrenia patients.

[1]  Henry A. Nasrallah,et al.  Schizophrenia, “Just the Facts”: What we know in 2008 Part 1: Overview , 2008, Schizophrenia Research.

[2]  Sophia Vinogradov,et al.  Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. , 2009, The American journal of psychiatry.

[3]  Melissa J. Green,et al.  Brain-derived neurotrophic factor levels in schizophrenia: a systematic review with meta-analysis , 2011, Molecular Psychiatry.

[4]  Sophia Vinogradov,et al.  Is Serum Brain-Derived Neurotrophic Factor a Biomarker for Cognitive Enhancement in Schizophrenia? , 2009, Biological Psychiatry.

[5]  G. Martinotti,et al.  Nerve growth factor and brain-derived neurotrophic factor concentrations in schizophrenia: a review. , 2012, Journal of biological regulators and homeostatic agents.

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

[7]  Menahem Segal,et al.  Role of neurotrophins in central synapse formation and stabilization , 2002, Nature Reviews Neuroscience.

[8]  Marc Laruelle,et al.  The Synaptic Hypothesis of Schizophrenia , 2003, Neuron.

[9]  J. González,et al.  Brain-Derived Neurotrophic Factor Val66Met and Psychiatric Disorders: Meta-Analysis of Case-Control Studies Confirm Association to Substance-Related Disorders, Eating Disorders, and Schizophrenia , 2007, Biological Psychiatry.

[10]  J. Lieberman,et al.  Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates. , 2000, The American journal of psychiatry.

[11]  E. Castrén,et al.  Sustained brain‐derived neurotrophic factor up‐regulation and sensorimotor gating abnormality induced by postnatal exposure to phencyclidine: comparison with adult treatment , 2006, Journal of neurochemistry.

[12]  Ruben C. Gur,et al.  A meta-analysis of emotion perception and functional outcomes in schizophrenia , 2012, Schizophrenia Research.

[13]  William A Banks,et al.  Transport of brain-derived neurotrophic factor across the blood–brain barrier , 1998, Neuropharmacology.

[14]  N. Andreasen,et al.  Cognitive deficits in recent-onset and chronic schizophrenia. , 2010, Journal of psychiatric research.

[15]  H. Thoenen,et al.  Molecular cloning and expression of brain-derived neurotrophic factor , 1989, Nature.

[16]  F. Angelucci,et al.  BDNF in schizophrenia, depression and corresponding animal models , 2005, Molecular Psychiatry.

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

[18]  S. Lawrie,et al.  Effects of the BDNF Val66Met polymorphism on neural responses to facial emotion , 2011, Psychiatry Research: Neuroimaging.

[19]  S. Kéri,et al.  The C270T polymorphism of the brain-derived neurotrophic factor gene is associated with schizophrenia , 2003, Schizophrenia Research.

[20]  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.

[21]  D. Souza,et al.  Reduced serum BDNF levels in schizophrenic patients on clozapine or typical antipsychotics. , 2007, Journal of psychiatric research.

[22]  H. Yamasue,et al.  No evidence for an association between the BDNF Val66Met polymorphism and schizophrenia or personality traits , 2006, Schizophrenia Research.

[23]  J. Gold Cognitive deficits as treatment targets in schizophrenia , 2004, Schizophrenia Research.

[24]  G. Taglialatela,et al.  Nerve growth factor and neuronal cell death , 2008, Molecular Neurobiology.

[25]  Sm,et al.  Risk Factors for , 2002 .

[26]  Y. Barde The nerve growth factor family. , 1990, Progress in growth factor research.

[27]  A. Mortimer,et al.  Can Antipsychotics Improve Social Cognition in Patients with Schizophrenia? , 2013, CNS Drugs.

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

[29]  Shitij Kapur,et al.  Specific and generalized neuropsychological deficits: a comparison of patients with various first-episode psychosis presentations. , 2010, The American journal of psychiatry.

[30]  T. Shinkai,et al.  No association between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case–control study and meta-analysis , 2007, Neuroscience Letters.

[31]  D. Lo Neurotrophic factors and synaptic plasticity , 1995, Neuron.

[32]  Alcino J. Silva,et al.  The molecular and cellular biology of enhanced cognition , 2009, Nature Reviews Neuroscience.

[33]  F. Kapczinski,et al.  Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis , 2013, BMC Psychiatry.

[34]  R. Heaton,et al.  Course of neurocognitive deficits in the prodrome and first episode of schizophrenia. , 2010, Neuropsychology.

[35]  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.

[36]  R. Murray,et al.  A quantitative association study between schizotypal traits and COMT, PRODH and BDNF genes in a healthy Chinese population , 2007, Psychiatry Research.

[37]  Peter F. Buckley,et al.  Neurotrophins and schizophrenia , 2007, Schizophrenia Research.

[38]  Jeffrey D Dawson,et al.  Association between brain-derived neurotrophic factor Val66Met gene polymorphism and progressive brain volume changes in schizophrenia. , 2007, The American journal of psychiatry.

[39]  F. Mosquera,et al.  Decreased levels of plasma BDNF in first-episode schizophrenia and bipolar disorder patients , 2006, Schizophrenia Research.

[40]  Kevin G Bath,et al.  Variant BDNF (Val66Met) impact on brain structure and function , 2006, Cognitive, affective & behavioral neuroscience.

[41]  Low BDNF is associated with cognitive impairment in chronic patients with schizophrenia , 2012, Psychopharmacology.

[42]  S. Leonard,et al.  Strain dependent effects of prenatal stress on gene expression in the rat hippocampus , 2011, Physiology & Behavior.

[43]  D. Lewis,et al.  Cortical inhibitory neurons and schizophrenia , 2005, Nature Reviews Neuroscience.

[44]  M. Ikeda,et al.  BDNF is not associated with schizophrenia: Data from a Japanese population study and meta-analysis , 2009, Schizophrenia Research.

[45]  Yong-Ku Kim,et al.  Increased Plasma Brain-Derived Neurotropic Factor, Not Nerve Growth Factor-Beta, in Schizophrenia Patients with Better Response to Risperidone Treatment , 2009, Neuropsychobiology.

[46]  T Bonhoeffer,et al.  Virus-mediated gene transfer into hippocampal CA1 region restores long-term potentiation in brain-derived neurotrophic factor mutant mice. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[47]  R. Murray,et al.  Risk factors for schizophrenia — All roads lead to dopamine , 2007, European Neuropsychopharmacology.

[48]  F. Aboitiz,et al.  Molecular mechanisms underlying glutamatergic dysfunction in schizophrenia: therapeutic implications , 2009, Journal of neurochemistry.

[49]  C A Jones,et al.  Animal models of schizophrenia , 2011, British journal of pharmacology.

[50]  Philip D. Harvey,et al.  Neuropsychological function and dysfunction in schizophrenia and psychotic affective disorders. , 2009, Schizophrenia bulletin.

[51]  B. Kolachana,et al.  Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Differentially Predicts Hippocampal Function in Medication-Free Patients with Schizophrenia , 2012, Molecular Psychiatry.

[52]  T. Sharma Characterisation of cognitive impairment in schizophrenia , 2003, The Lancet Neurology.

[53]  K. Felmingham,et al.  The functional epistasis of 5-HTTLPR and BDNF Val66Met on emotion processing: a preliminary study , 2012, Brain and behavior.

[54]  E. Tongiorgi,et al.  Low serum truncated-BDNF isoform correlates with higher cognitive impairment in schizophrenia. , 2011, Journal of psychiatric research.

[55]  Abraham Weizman,et al.  The possible role of neurotrophins in the pathogenesis and therapy of schizophrenia , 2005, European Neuropsychopharmacology.

[56]  Michael F. Green,et al.  The MATRICS initiative: developing a consensus cognitive battery for clinical trials , 2004, Schizophrenia Research.

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

[58]  R. Kahn,et al.  Polymorphisms in the brain-derived neurotrophic factor gene are not associated with either anorexia nervosa or schizophrenia in Dutch patients. , 2005, Psychiatric genetics.

[59]  Z. Daskalakis,et al.  The role of BDNF in the pathophysiology and treatment of schizophrenia. , 2012, Journal of psychiatric research.

[60]  D. Penn,et al.  Deficits in domains of social cognition in schizophrenia: a meta-analysis of the empirical evidence. , 2013, Schizophrenia bulletin.

[61]  J. Savitz,et al.  The molecular genetics of cognition: dopamine, COMT and BDNF , 2006, Genes, brain, and behavior.

[62]  H. Nawa,et al.  Decreased levels of brain-derived neurotrophic factor in serum of chronic schizophrenic patients , 2002, Psychiatry Research.

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

[64]  D. Marchant,et al.  Risk factors. , 1994, Obstetrics and gynecology clinics of North America.

[65]  D. Clair,et al.  Genetic variants in the BDNF gene and therapeutic response to risperidone in schizophrenia patients: a pharmacogenetic study , 2010, European Journal of Human Genetics.

[66]  S. Cichon,et al.  Evidence for a Relationship Between Genetic Variants at the Brain-Derived Neurotrophic Factor (BDNF) Locus and Major Depression , 2005, Biological Psychiatry.

[67]  J. Kleinman,et al.  Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia , 2003, Molecular Psychiatry.

[68]  Sarah A. J. Reading,et al.  Neurobiology of Schizophrenia , 2006, Neuron.

[69]  X. Zhang,et al.  Decreased BDNF in serum of patients with chronic schizophrenia on long-term treatment with antipsychotics , 2005, Neuroscience Letters.

[70]  T. Kosten,et al.  Decreased levels of serum brain-derived neurotrophic factor in drug-naïve first-episode schizophrenia: relationship to clinical phenotypes , 2009, Psychopharmacology.

[71]  E. Rizos,et al.  Investigation of serum BDNF levels in drug-naive patients with schizophrenia , 2008, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[72]  Michael F. Green,et al.  Identifying Cognitive Mechanisms Targeted for Treatment Development in Schizophrenia: An Overview of the First Meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative , 2008, Biological Psychiatry.

[73]  T. Lehtimäki,et al.  Lack of association between two polymorphisms of brain-derived neurotrophic factor and response to typical neuroleptics , 2005, Journal of Neural Transmission.

[74]  H. Thoenen,et al.  Neurotrophin-6 is a new member of the nerve growth factor family , 1994, Nature.

[75]  D. Ginty,et al.  Functions and mechanisms of retrograde neurotrophin signalling , 2005, Nature Reviews Neuroscience.

[76]  M. Krebs,et al.  Age at onset of schizophrenia: interaction between brain-derived neurotrophic factor and dopamine D3 receptor gene variants , 2005, Neuroreport.

[77]  L. Abramova,et al.  Association of the Val66Met polymorphism of the brain-derived neurotrophic factor gene with schizophrenia in Russians , 2008, Molecular Biology.

[78]  Y. Barde,et al.  Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family , 1990, Nature.

[79]  W B Levy,et al.  Spatial overlap between populations of synapses determines the extent of their associative interaction during the induction of long-term potentiation and depression. , 1990, Journal of neurophysiology.

[80]  T. Hökfelt,et al.  TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus , 2011, Proceedings of the National Academy of Sciences.

[81]  Chen Zhang,et al.  Association Between BDNF Val66Met Polymorphism and Cognitive Performance in Antipsychotic-Naïve Patients with Schizophrenia , 2012, Journal of Molecular Neuroscience.

[82]  E. McAuley,et al.  Brain-Derived Neurotrophic Factor Is Associated with Age-Related Decline in Hippocampal Volume , 2010, The Journal of Neuroscience.

[83]  O. Guillin,et al.  Brain-derived neurotrophic factor in schizophrenia and its relation with dopamine. , 2007, International review of neurobiology.

[84]  M. Keshavan,et al.  Schizophrenia, “just the facts”: What we know in 2008 Part 3: Neurobiology , 2008, Schizophrenia Research.

[85]  L. Mei,et al.  Synaptic dysfunction in schizophrenia. , 2012, Advances in experimental medicine and biology.

[86]  Erik G. Jönsson,et al.  Brain-derived neurotrophic factor gene (BDNF) variants and schizophrenia: An association study , 2006, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[87]  M. Pedrini,et al.  Serum brain-derived neurotrophic factor and clozapine daily dose in patients with schizophrenia: A positive correlation , 2011, Neuroscience Letters.

[88]  Robin M. Murray,et al.  Schizophrenia: From developmental deviance to dopamine dysregulation , 2008, European Neuropsychopharmacology.

[89]  M. Tsuang,et al.  Meta-analysis reveals no association of the Val66Met polymorphism of brain-derived neurotrophic factor with either schizophrenia or bipolar disorder , 2007, Psychiatric genetics.

[90]  H. Nasrallah,et al.  Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. , 2010, The international journal of neuropsychopharmacology.

[91]  A. Grace,et al.  Impaired brain development in the rat following prenatal exposure to methylazoxymethanol acetate at gestational day 17 and neurotrophin distribution , 2004, Neuroreport.

[92]  S. Leonard,et al.  Prenatal stress differentially alters brain-derived neurotrophic factor expression and signaling across rat strains , 2011, Neuroscience.

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

[94]  N. Siafakas,et al.  Association of Serum Brain-Derived Neurotrophic Factor and Duration of Untreated Psychosis in First-Episode Patients with Schizophrenia , 2010, Neuropsychobiology.

[95]  P. Stratta,et al.  COMT Val158Met and BDNF C270T polymorphisms in schizophrenia: a case-control study , 2005, Schizophrenia Research.

[96]  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.

[97]  P. Stratta,et al.  COMT Val(158)Met and BDNF C(270)T polymorphisms in schizophrenia: a case-control study. , 2005, Schizophrenia research.

[98]  H. Danker-Hopfe,et al.  Brain-derived neurotrophic factor serum concentrations are increased in drug-naïve schizophrenic patients with chronic cannabis abuse and multiple substance abuse , 2004, Neuroscience Letters.

[99]  S. Tsai,et al.  An association study of a brain-derived neurotrophic factor Val66Met polymorphism and clozapine response of schizophrenic patients , 2003, Neuroscience Letters.

[100]  Lin He,et al.  Association between the brain-derived neurotrophic factor (BDNF) gene and Schizophrenia in the Chinese population , 2006, Neuroscience Letters.

[101]  N. Akarsu,et al.  The effect of depression, BDNF gene val66met polymorphism and gender on serum BDNF levels , 2010, Brain Research Bulletin.

[102]  Chunbo Li,et al.  Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review , 2012, Shanghai archives of psychiatry.

[103]  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.

[104]  Robert Zöchling,et al.  Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses , 2001, Schizophrenia Research.

[105]  J. Hauser,et al.  Association analysis of brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective disorder , 2004, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[106]  J. Hauser,et al.  No association of the brain-derived neurotrophic factor (BDNF) gene C-270T polymorphism with schizophrenia , 2005, Schizophrenia Research.

[107]  J. Thome,et al.  Neurotrophic factors and the pathophysiology of schizophrenic psychoses , 2004, European Psychiatry.

[108]  D. Matsuzawa,et al.  Associations of serum brain-derived neurotrophic factor with cognitive impairments and negative symptoms in schizophrenia , 2011, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[109]  R. Hashimoto,et al.  No association between the Val66Met polymorphism of the brain-derived neurotrophic factor gene and bipolar disorder in a Japanese population: A multicenter study , 2004, Biological Psychiatry.

[110]  K Maeda,et al.  Abnormal expression of brain-derived neurotrophic factor and its receptor in the corticolimbic system of schizophrenic patients , 2000, Molecular Psychiatry.

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

[112]  Zhijun Zhang,et al.  Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls , 2012, Human Genetics.

[113]  P. Nikolaidou,et al.  Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naive schizophrenic patients , 2011, Schizophrenia Research.

[114]  L. Belluscio,et al.  Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. , 1990, Science.