title: Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice.
abstract: Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1+/-) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1+/-mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1+/-mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1+/-mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments.
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada; Department of Rehabilitation Sciences, Hong Kong Polytechnic University, Hong Kong, SAR, China.
authors.forename: S Y
authors.initials: SY
authors.lastname: Yau
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: C A
authors.initials: CA
authors.lastname: Bostrom
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Chiu
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: C J
authors.initials: CJ
authors.lastname: Fontaine
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Sawchuk
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Meconi
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: R C
authors.initials: RC
authors.lastname: Wortman
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Truesdell
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Truesdell
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Chiu
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: B N
authors.initials: BN
authors.lastname: Hryciw
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: B D
authors.initials: BD
authors.lastname: Eadie
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Ghilan
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada. Electronic address: brain64@uvic.ca.
authors.forename: B R
authors.initials: BR
authors.lastname: Christie
mesh_terms: D000818:Animals; D018891:Dentate Gyrus / Q000473:pathology*; D004195:Disease Models, Animal; D030762:Estrous Cycle / Q000187:drug effects / Q000235:genetics; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D005838:Genotype; D005998:Glycine / Q000627:therapeutic use; D019417:Hindlimb Suspension; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013550:Swimming / Q000523:psychology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D005998:Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D014633:Valine; C497684:Fmr1 protein, mouse; C056639:2-amino-5-phosphopentanoic acid
keywords: Females; Fragile X syndrome; Hippocampus; Learning and memory; Synaptic plasticity