Fibroblast Growth Factors in Neurodevelopment and Psychopathology

In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.

[1]  R. Kahn,et al.  Brain volumes in schizophrenia: a meta-analysis in over 18 000 subjects. , 2013, Schizophrenia bulletin.

[2]  Tao Li,et al.  FGFR2 is associated with bipolar disorder: A large-scale case–control study of three psychiatric disorders in the Chinese Han population , 2012, The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry.

[3]  H. Akil,et al.  Neonatal fibroblast growth factor treatment enhances cocaine sensitization , 2012, Pharmacology Biochemistry and Behavior.

[4]  Amelia J. Eisch,et al.  Depression and Hippocampal Neurogenesis: A Road to Remission? , 2012, Science.

[5]  Stanley J. Watson,et al.  The Fibroblast Growth Factor Family: Neuromodulation of Affective Behavior , 2012, Neuron.

[6]  P. Licznerski,et al.  Antidepressant Effects of Fibroblast Growth Factor-2 in Behavioral and Cellular Models of Depression , 2012, Biological Psychiatry.

[7]  M. Stachowiak,et al.  Fibroblast growth factor 2 regulates dopaminergic neuron development in vivo , 2012, Journal of neurochemistry.

[8]  F. Vaccarino,et al.  Learning and Memory Depend on Fibroblast Growth Factor Receptor 2 Functioning in Hippocampus , 2012, Biological Psychiatry.

[9]  A. Buonanno,et al.  The Importance of the NRG-1/ErbB4 Pathway for Synaptic Plasticity and Behaviors Associated with Psychiatric Disorders , 2012, Journal of Neuroscience.

[10]  Oscar Marín,et al.  Interneuron dysfunction in psychiatric disorders , 2012, Nature Reviews Neuroscience.

[11]  K. Fuxe,et al.  Fibroblast Growth Factor Receptor 1– 5-Hydroxytryptamine 1A Heteroreceptor Complexes and Their Enhancement of Hippocampal Plasticity , 2012, Biological Psychiatry.

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

[13]  Qi Xu,et al.  Common variants on 8p12 and 1q24.2 confer risk of schizophrenia , 2011, Nature Genetics.

[14]  Akira Sawa,et al.  Linking neurodevelopmental and synaptic theories of mental illness through DISC1 , 2011, Nature Reviews Neuroscience.

[15]  E. Courchesne,et al.  Neuron number and size in prefrontal cortex of children with autism. , 2011, JAMA.

[16]  Huangui Xiong,et al.  FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders , 2011, Proceedings of the National Academy of Sciences.

[17]  Nicolas Rohner,et al.  Modulation of Fgfr1a Signaling in Zebrafish Reveals a Genetic Basis for the Aggression–Boldness Syndrome , 2011, The Journal of Neuroscience.

[18]  C. Grothe,et al.  FGF-2 Deficiency Does Not Influence FGF Ligand and Receptor Expression during Development of the Nigrostriatal System , 2011, PloS one.

[19]  T. Jay,et al.  Factoring neurotrophins into a neurite-based pathophysiological model of schizophrenia , 2011, Progress in Neurobiology.

[20]  Robert C. Thompson,et al.  Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals , 2011, Proceedings of the National Academy of Sciences.

[21]  H. Akil,et al.  Short-Hairpin RNA Silencing of Endogenous Fibroblast Growth Factor 2 in Rat Hippocampus Increases Anxiety Behavior , 2011, Biological Psychiatry.

[22]  N. Itoh,et al.  Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. , 2011, Journal of biochemistry.

[23]  K. Unsicker,et al.  Roles of exogenous and endogenous FGF-2 in animal models of depression. , 2011, Restorative neurology and neuroscience.

[24]  F. Vaccarino,et al.  Fibroblast growth factor receptor 1 (Fgfr1) participates in postnatal interneuron development , 2010, International Journal of Developmental Neuroscience.

[25]  R. Kahn,et al.  Fibroblast growth factors in schizophrenia. , 2010, Schizophrenia bulletin.

[26]  K. Unsicker,et al.  Expression and Functions of Fibroblast Growth Factor 2 (FGF-2) in Hippocampal Formation , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[27]  F. Vaccarino,et al.  Neural Stem Cell Regulation, Fibroblast Growth Factors, and the Developmental Origins of Neuropsychiatric Disorders , 2010, Front. Neurosci..

[28]  T. Horvath,et al.  Fgfr2 Is Required for the Development of the Medial Prefrontal Cortex and Its Connections with Limbic Circuits , 2010, The Journal of Neuroscience.

[29]  D. Volk,et al.  Prefrontal cortical circuits in schizophrenia. , 2010, Current topics in behavioral neurosciences.

[30]  Martin P Paulus,et al.  The quantitative assessment of motor activity in mania and schizophrenia. , 2010, Journal of affective disorders.

[31]  A. Serretti,et al.  Effect of basic fibroblast growth factor (FGF2) gene polymorphisms on SSRIs treatment response and side effects , 2009, European Neuropsychopharmacology.

[32]  A. Kozubík,et al.  Molecular pathology of the fibroblast growth factor family , 2009, Human mutation.

[33]  J. Dziewia̧tkowski,et al.  Serotonergic hyperinnervation and effective serotonin blockade in an FGF receptor developmental model of psychosis , 2009, Schizophrenia Research.

[34]  B. Bogerts,et al.  Glial cells in schizophrenia: pathophysiological significance and possible consequences for therapy , 2009, Expert review of neurotherapeutics.

[35]  H. Akil,et al.  A New Role for FGF2 as an Endogenous Inhibitor of Anxiety , 2009, The Journal of Neuroscience.

[36]  Angus W MacDonald,et al.  What we know: findings that every theory of schizophrenia should explain. , 2009, Schizophrenia bulletin.

[37]  R. Hevner,et al.  Fibroblast growth factor signaling in development of the cerebral cortex , 2009, Development, growth & differentiation.

[38]  M. Mohammadi,et al.  The FGF family: biology, pathophysiology and therapy , 2009, Nature Reviews Drug Discovery.

[39]  H. Akil,et al.  Neonatal FGF2 alters cocaine self-administration in the adult rat , 2009, Pharmacology Biochemistry and Behavior.

[40]  E. Grigorenko,et al.  Regulation of Cerebral Cortical Size and Neuron Number by Fibroblast Growth Factors: Implications for Autism , 2009, Journal of autism and developmental disorders.

[41]  D. Fernig,et al.  Extracellular interactome of the FGF receptor–ligand system: Complexities and the relative simplicity of the worm , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[42]  L. Ment,et al.  Fgfr1 Is Required for Cortical Regeneration and Repair after Perinatal Hypoxia , 2009, The Journal of Neuroscience.

[43]  M C O'Donovan,et al.  Analysis of 10 independent samples provides evidence for association between schizophrenia and a SNP flanking fibroblast growth factor receptor 2 , 2009, Molecular Psychiatry.

[44]  Marc Flajolet,et al.  FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity , 2008, Nature Neuroscience.

[45]  V. Berezin,et al.  Signaling mechanisms of neurite outgrowth induced by the cell adhesion molecules NCAM and N-Cadherin , 2008, Cellular and Molecular Life Sciences.

[46]  H. Akil,et al.  Antidepressant-like effects of intracerebroventricular FGF2 in rats , 2008, Brain Research.

[47]  Ge-lin Xu,et al.  Intranasal bFGF-induced progenitor cell proliferation and neuroprotection after transient focal cerebral ischemia , 2008, Neuroscience Letters.

[48]  R. Leurs,et al.  Interactions between histamine H3 and dopamine D2 receptors and the implications for striatal function , 2008, Neuropharmacology.

[49]  M. Picciotto,et al.  Deficiency in Inhibitory Cortical Interneurons Associates with Hyperactivity in Fibroblast Growth Factor Receptor 1 Mutant Mice , 2008, Biological Psychiatry.

[50]  L. Mucke,et al.  Abnormal social behaviors in mice lacking Fgf17 , 2008, Genes, brain, and behavior.

[51]  P. Mortensen,et al.  Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. , 2008, Archives of general psychiatry.

[52]  D. Frost,et al.  The fibroblast growth factor system is downregulated following social defeat , 2008, Neuroscience Letters.

[53]  C. Deng,et al.  Fibroblast Growth Factor Receptor-1 is Required for Long-Term Potentiation, Memory Consolidation, and Neurogenesis , 2007, Biological Psychiatry.

[54]  M. Collu,et al.  Reduction of Corticostriatal Glutamatergic Fibers in Basic Fibroblast Growth Factor Deficient Mice is Associated with Hyperactivity and Enhanced Dopaminergic Transmission , 2007, Biological Psychiatry.

[55]  Ivor Mason,et al.  Initiation to end point: the multiple roles of fibroblast growth factors in neural development , 2007, Nature Reviews Neuroscience.

[56]  B. Kolb,et al.  Pre- and postnatal FGF-2 both facilitate recovery and alter cortical morphology following early medial prefrontal cortical injury , 2007, Behavioural Brain Research.

[57]  S. Maier,et al.  Stress-induced glucocorticoids suppress the antisense molecular regulation of FGF-2 expression , 2007, Psychoneuroendocrinology.

[58]  J. Rubenstein,et al.  Patterning of frontal cortex subdivisions by Fgf17 , 2007, Proceedings of the National Academy of Sciences.

[59]  C. Grothe,et al.  The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system , 2007, Brain Research Reviews.

[60]  S. Maier,et al.  Expression of fibroblast growth factor-2 and brain-derived neurotrophic factor mRNA in the medial prefrontal cortex and hippocampus after uncontrollable or controllable stress , 2007, Neuroscience.

[61]  Esther Lipokatic-Takacs,et al.  Fibroblast Growth Factor (FGF)-2 and FGF Receptor 3 Are Required for the Development of the Substantia Nigra, and FGF-2 Plays a Crucial Role for the Rescue of Dopaminergic Neurons after 6-Hydroxydopamine Lesion , 2007, The Journal of Neuroscience.

[62]  K. Nave,et al.  Mice with Conditional Inactivation of Fibroblast Growth Factor Receptor-2 Signaling in Oligodendrocytes Have Normal Myelin But Display Dramatic Hyperactivity when Combined with Cnp1 Inactivation , 2006, The Journal of Neuroscience.

[63]  P. Sedgwick,et al.  Hippocampal FGF-2 and FGFR1 mRNA expression in major depression, schizophrenia and bipolar disorder , 2006, Brain Research Bulletin.

[64]  H. Akil,et al.  The Fibroblast Growth Factor System and Mood Disorders , 2006, Biological Psychiatry.

[65]  R. Hard,et al.  Fibroblast growth factor receptor signaling affects development and function of dopamine neurons – inhibition results in a schizophrenia‐like syndrome in transgenic mice , 2006, Journal of neurochemistry.

[66]  K. Unsicker,et al.  FGF‐2 deficiency does not alter vulnerability of the dopaminergic nigrostriatal system towards MPTP intoxication in mice , 2006, The European journal of neuroscience.

[67]  F. Fumagalli,et al.  Prenatal stress elicits regionally selective changes in basal FGF-2 gene expression in adulthood and alters the adult response to acute or chronic stress , 2005, Neurobiology of Disease.

[68]  D. Brat,et al.  The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[69]  V. Haroutunian,et al.  Variations in differential gene expression patterns across multiple brain regions in schizophrenia , 2005, Schizophrenia Research.

[70]  C. Vorhees,et al.  Abnormal neurodevelopment, neurosignaling and behaviour in Npas3‐deficient mice , 2005, The European journal of neuroscience.

[71]  D. Fortin,et al.  Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage , 2005, The Journal of Neuroscience.

[72]  F. Fumagalli,et al.  Emerging role of the FGF system in psychiatric disorders. , 2005, Trends in pharmacological sciences.

[73]  Dafang Wu Neuroprotection in experimental stroke with targeted neurotrophins , 2005 .

[74]  J. Partanen,et al.  Fibroblast Growth Factor Receptor 1 Is Required for the Proliferation of Hippocampal Progenitor Cells and for Hippocampal Growth in Mouse , 2022 .

[75]  JaneR . Taylor,et al.  Loss of Glutamatergic Pyramidal Neurons in Frontal and Temporal Cortex Resulting from Attenuation of Fgfr1 Signaling Is Associated with Spontaneous Hyperactivity in Mice , 2022 .

[76]  K. Hashimoto,et al.  Increased levels of serum basic fibroblast growth factor in schizophrenia , 2003, Psychiatry Research.

[77]  Bernhard Reuss,et al.  Fibroblast growth factors and their receptors in the central nervous system , 2003, Cell and Tissue Research.

[78]  D W Cox,et al.  Disruption of the neuronal PAS3 gene in a family affected with schizophrenia , 2003, Journal of medical genetics.

[79]  Rosanna Dono,et al.  Fibroblast growth factors as regulators of central nervous system development and function. , 2003, American journal of physiology. Regulatory, integrative and comparative physiology.

[80]  Masashi Suzuki,et al.  Fibroblast growth factor‐2 increases functional excitatory synapses on hippocampal neurons , 2002, The European journal of neuroscience.

[81]  F. Vaccarino,et al.  Chronic hypoxia up-regulates fibroblast growth factor ligands in the perinatal brain and induces fibroblast growth factor-responsive radial glial cells in the sub-ependymal zone , 2002, Neuroscience.

[82]  I. Gottesman,et al.  The glial growth factors deficiency and synaptic destabilization hypothesis of schizophrenia , 2002, BMC psychiatry.

[83]  Peter B. Jones,et al.  Obstetric complications and schizophrenia: historical and meta-analytic review. , 2002, The American journal of psychiatry.

[84]  H. Miyake,et al.  Fibroblast Growth Factors and Their Receptors in Oligodendrocyte Development: Implications for Demyelination and Remyelination , 2002, Developmental Neuroscience.

[85]  E. Zackai,et al.  Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. , 2002, American journal of human genetics.

[86]  F. Vaccarino,et al.  Fibroblast Growth Factor 2 Is Necessary for the Growth of Glutamate Projection Neurons in the Anterior Neocortex , 2002, The Journal of Neuroscience.

[87]  Klaus P. Ebmeier,et al.  Right and left prefrontal transcranial magnetic stimulation at 1 Hz does not affect mood in healthy volunteers , 2002, BMC psychiatry.

[88]  F. Fumagalli,et al.  Modulation of fibroblast growth factor-2 by stress and corticosteroids: from developmental events to adult brain plasticity , 2001, Brain Research Reviews.

[89]  Y. Yamaguchi,et al.  Heparan sulfate proteoglycans in the nervous system: their diverse roles in neurogenesis, axon guidance, and synaptogenesis. , 2001, Seminars in cell & developmental biology.

[90]  H. Haas,et al.  The physiology of brain histamine , 2001, Progress in Neurobiology.

[91]  Nobuyuki Itoh,et al.  Fibroblast growth factors , 2001, Genome Biology.

[92]  A Carlsson,et al.  Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. , 2001, Annual review of pharmacology and toxicology.

[93]  J. Leckman,et al.  Basic Fibroblast Growth Factor (Fgf2) Is Necessary for Cell Proliferation and Neurogenesis in the Developing Cerebral Cortex , 2000, The Journal of Neuroscience.

[94]  J. Stewart,et al.  Changes in astrocytic basic fibroblast growth factor expression during and after prolonged exposure to escalating doses of amphetamine , 2000, Neuroscience.

[95]  J. Fallon,et al.  Fibroblast growth factors as multifunctional signaling factors. , 1999, International review of cytology.

[96]  R. Zeller,et al.  Impaired cerebral cortex development and blood pressure regulation in FGF‐2‐deficient mice , 1998, The EMBO journal.

[97]  S. Tsang,et al.  Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[98]  S. Pawlowski,et al.  Fibroblast growth factor 2 control of vascular tone , 1998, Nature Medicine.

[99]  P. Rosique,et al.  Psychometric analysis in children with mental retardation due to perinatal hypoxia treated with fibroblast growth factor (FGF) and showing improvement in mental development. , 2008, Journal of intellectual disability research : JIDR.