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Title: Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmrl heterozygous knockout mice
Authors: Yau, SY 
Bostrom, CA
Chiu, J
Fontaine, CJ
Sawchuk, S
Meconi, A
Wortman, RC
Truesdell, E
Truesdell, A
Chiu, C
Hryciw, BN
Eadie, BD
Ghilan, M
Christie, BR
Issue Date: Dec-2016
Source: Neurobiology of disease, Dec. 2016, v. 96, p. 261-270
Abstract: Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmrl 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 Fmrl 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 Fmrl knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmrl 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.
Keywords: Fragile X syndrome
Females
Hippocampus
Learning and memory
Synaptic plasticity
Publisher: Academic Press
Journal: Neurobiology of disease 
ISSN: 0969-9961
EISSN: 1095-953X
DOI: 10.1016/j.nbd.2016.09.012
Rights: © 2016 Elsevier Inc. All rights reserved.
© 2016. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
The following publication Yau, S. Y., Bostrom, C. A., Chiu, J., Fontaine, C. J., Sawchuk, S., Meconi, A., ... & Christie, B. R. (2016). Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice. Neurobiology of disease, 96, 261-270 is available at https://doi.org/10.1016/j.nbd.2016.09.012.
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