title: Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome.
abstract: Fragile-X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading genetic cause of autism spectrum disorder. FXS is caused by transcriptional silencing of the Fragile X Mental Retardation 1 (Fmr1) gene due to a CGG repeat expansion, resulting in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is involved in transcriptional regulation and trafficking of mRNA from the nucleus to the cytoplasm and distal sites both in pre- and post-synaptic terminals. Consequently, FXS is a multifaceted disorder associated with impaired synaptic plasticity. One region of the brain that is significantly impacted by the loss of FMRP is the hippocampus, a structure that plays a critical role in the regulation of mood and cognition. This review provides an overview of the neuropathology of Fragile-X Syndrome, highlighting how structural and synaptic deficits in hippocampal subregions, including the CA1 exhibiting exaggerated metabotropic glutamate receptor dependent long-term depression and the dentate gyrus displaying hypofunction of N-methyl-d-aspartate receptors, contribute to cognitive impairments associated with this neurodevelopmental disorder.
authors.affiliation: Division of Medical Sciences, University of Victoria, Canada.
authors.forename: Crystal
authors.initials: C
authors.lastname: Bostrom
authors.affiliation: Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong, Hong Kong.
authors.forename: Suk-Yu
authors.initials: SY
authors.lastname: Yau
authors.affiliation: Division of Medical Sciences, University of Victoria, Canada.
authors.forename: Namat
authors.initials: N
authors.lastname: Majaess
authors.affiliation: Division of Medical Sciences, University of Victoria, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Vetrici
authors.affiliation: Division of Medical Sciences, University of Victoria, Canada; Island Medical Program, University of British Columbia, Victoria, B.C., Canada.
authors.forename: Joana
authors.initials: J
authors.lastname: Gil-Mohapel
authors.affiliation: Division of Medical Sciences, University of Victoria, Canada; Island Medical Program, University of British Columbia, Victoria, B.C., Canada. Electronic address: brain64@uvic.ca.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Christie
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder; D060825:Cognitive Dysfunction; D051860:Fragile X Messenger Ribonucleoprotein 1; D005600:Fragile X Syndrome; D006624:Hippocampus; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Fmr1 knock-out mice; Fragile-X Syndrome; Hippocampus; NMDA receptor; Synaptic plasticity; mGluR theory