Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging

Fragile X Syndrome (FXS) is the most common single gene cause of inherited mental impairment, and cognitive deficits can range from simple learning disabilities to mental retardation. Human FXS is caused by a loss of the Fragile X Mental Retardation Protein (FMRP). The fragile X knockout (FX KO) mouse also shows a loss of FMRP, as well as many of the physical and behavioural characteristics of human FXS. This work aims to characterize the anatomical changes between the FX KO and a corresponding wild type mouse. Significant volume decreases were found in two regions within the deep cerebellar nuclei, namely the nucleus interpositus and the fastigial nucleus, which may be caused by a loss of neurons as indicated by histological analysis. Well-known links between these nuclei and previously established behavioural and physical characteristics of FXS are discussed. The loss of FMRP has a significant effect on these two nuclei, and future studies of FXS should evaluate the biochemical, physiological, and behavioral consequences of alterations in these key nuclei.

[1]  Jacqueline Blundell,et al.  A Neuroligin-3 Mutation Implicated in Autism Increases Inhibitory Synaptic Transmission in Mice , 2007, Science.

[2]  Stephen T Warren,et al.  A decade of molecular studies of fragile X syndrome. , 2002, Annual review of neuroscience.

[3]  S. T. Warren,et al.  Fragile X mouse: strain effects of knockout phenotype and evidence suggesting deficient amygdala function , 1999, Neuroscience.

[4]  Karel Svoboda,et al.  Abnormal Development of Dendritic Spines inFMR1 Knock-Out Mice , 2001, The Journal of Neuroscience.

[5]  Michael Gruss,et al.  Alterations of Amino Acids and Monoamine Metabolism in Male Fmr1 Knockout Mice: A Putative Animal Model of the Human Fragile X Mental Retardation Syndrome , 2001, Neural plasticity.

[6]  R. Mark Henkelman,et al.  In vivo multiple‐mouse MRI at 7 Tesla , 2005, Magnetic resonance in medicine.

[7]  D. Le Bihan,et al.  Diffusion tensor imaging: Concepts and applications , 2001, Journal of magnetic resonance imaging : JMRI.

[8]  Thomas E. Nichols,et al.  Thresholding of Statistical Maps in Functional Neuroimaging Using the False Discovery Rate , 2002, NeuroImage.

[9]  H. Noda,et al.  Afferent and efferent connections of the oculomotor cerebellar vermis in the macaque monkey , 1987, The Journal of comparative neurology.

[10]  R. Mark Henkelman,et al.  Automated deformation analysis in the YAC128 Huntington disease mouse model , 2008, NeuroImage.

[11]  E. De Schutter,et al.  Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome , 2005, Neuron.

[12]  Kiralee M. Hayashi,et al.  Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP) , 2008, Annals of neurology.

[13]  S. Lawrie,et al.  Towards a neuroanatomy of autism: A systematic review and meta-analysis of structural magnetic resonance imaging studies , 2008, European Psychiatry.

[14]  Dana C Crawford,et al.  FMR1 and the fragile X syndrome: Human genome epidemiology review , 2001, Genetics in Medicine.

[15]  Guy Nagels,et al.  Fmr1 knockout mice: A model to study fragile X mental retardation , 1994, Cell.

[16]  Jan Sijbers,et al.  Neuroanatomy of the fragile X knockout mouse brain studied using in vivo high resolution magnetic resonance imaging , 1999, European Journal of Human Genetics.

[17]  J H Freeman,et al.  Developmental Changes in Eye-Blink Conditioning and Neuronal Activity in the Cerebellar Interpositus Nucleus , 2000, The Journal of Neuroscience.

[18]  A T Hoogeveen,et al.  Animal model for fragile X syndrome. , 1997, Annals of medicine.

[19]  R. Mark Henkelman,et al.  High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice , 2008, NeuroImage.

[20]  Joseph Piven,et al.  Early white‐matter abnormalities of the ventral frontostriatal pathway in fragile X syndrome , 2009, Developmental medicine and child neurology.

[21]  Richard F. Thompson,et al.  The role of the cerebellum in classical conditioning of discrete behavioral responses , 2009, Neuroscience.

[22]  Allan L. Reiss,et al.  Neurodevelopmental effects of the FMR-1 full mutation in humans , 1995, Nature Medicine.

[23]  Leila Baghdadi,et al.  Presentation of 3D isotropic imaging data for optimal viewing , 2006, Magnetic resonance in medicine.

[24]  W. Greenough,et al.  Dendritic spine structural anomalies in fragile-X mental retardation syndrome. , 2000, Cerebral cortex.

[25]  V. Menon,et al.  White matter tract alterations in fragile X syndrome: Preliminary evidence from diffusion tensor imaging , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[26]  Michael Gruss,et al.  Age- and region-specific imbalances of basal amino acids and monoamine metabolism in limbic regions of female Fmr1 knock-out mice , 2004, Neurochemistry International.

[27]  D. Collins,et al.  Automatic 3D Intersubject Registration of MR Volumetric Data in Standardized Talairach Space , 1994, Journal of computer assisted tomography.

[28]  Philippe Séguéla,et al.  Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. , 2009, Cerebral cortex.

[29]  Bibiana Scelfo,et al.  The Cerebellum: Synaptic Changes and Fear Conditioning , 2005, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[30]  Stephen T Warren,et al.  Fragile X Syndrome: An Update and Review for the Primary Pediatrician , 2005, Clinical pediatrics.

[31]  Allan L Reiss,et al.  The neuroanatomy and neuroendocrinology of fragile X syndrome. , 2004, Mental retardation and developmental disabilities research reviews.

[32]  R. D'Hooge,et al.  Fmr1 knockout mice: A model to study fragile X mental retardation , 1994, Cell.

[33]  Allan L. Reiss,et al.  Neuroanatomy of fragile X syndrome , 1994, Neurology.

[34]  David R. Hampson,et al.  Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures , 2009, Molecular Pharmacology.

[35]  W. Brown,et al.  Fmr1 knockout mouse has a distinctive strain-specific learning impairment , 2000, Neuroscience.

[36]  Raffaele Ferri,et al.  Audiogenic Seizures Susceptibility in Transgenic Mice with Fragile X Syndrome , 2000, Epilepsia.

[37]  L. Doering,et al.  Astrocytes Prevent Abnormal Neuronal Development in the Fragile X Mouse , 2010, The Journal of Neuroscience.

[38]  A L Reiss,et al.  Neuroanatomy in fragile X females: the posterior fossa. , 1991, American journal of human genetics.

[39]  R. Mark Henkelman,et al.  Sexual dimorphism revealed in the structure of the mouse brain using three-dimensional magnetic resonance imaging , 2007, NeuroImage.

[40]  A L Reiss,et al.  Decreased cerebellar posterior vermis size in fragile X syndrome , 1998, Neurology.

[41]  L. Doering,et al.  Developmental expression of FMRP in the astrocyte lineage: Implications for fragile X syndrome , 2007, Glia.

[42]  W. Greenough,et al.  Hippocampal pyramidal cells in adult Fmr1 knockout mice exhibit an immature-appearing profile of dendritic spines , 2006, Brain Research.

[43]  Michael Lardelli,et al.  Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. , 2006, Human molecular genetics.

[44]  R Mark Henkelman,et al.  Anatomical phenotyping in the brain and skull of a mutant mouse by magnetic resonance imaging and computed tomography. , 2006, Physiological genomics.

[45]  Alan C. Evans,et al.  Automatic "pipeline" analysis of 3-D MRI data for clinical trials: application to multiple sclerosis , 2002, IEEE Transactions on Medical Imaging.

[46]  A L Reiss,et al.  Preliminary communication: neuroanatomical variations of the posterior fossa in men with the fragile X (Martin-Bell) syndrome. , 1988, American journal of medical genetics.

[47]  E. Courchesne,et al.  Hypoplasia of cerebellar vermal lobules VI and VII in autism. , 1988, The New England journal of medicine.