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Fragile X mice: Reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus

Authors

  • Sung Hwan Yun,

    1. Departments of Pediatrics and Research, Maimonides Medical Center, Brooklyn, New York
    2. NorthShore University HealthSystem Research Institute, Evanston, Illinois
    3. Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois
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  • Barbara L. Trommer

    Corresponding author
    1. Departments of Pediatrics and Research, Maimonides Medical Center, Brooklyn, New York
    2. NorthShore University HealthSystem Research Institute, Evanston, Illinois
    3. Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois
    4. Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York
    • Department of Pediatrics, Maimonides Medical Center, 4802 10th Ave., Brooklyn, NY 11219
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Abstract

Fragile X syndrome (FXS) is a monogenic mental retardation syndrome that frequently includes autism. The Fmr1-knockout (Fmr1-KO) mouse, like FXS-affected individuals, lacks the fragile X mental retardation protein (FMRP) and models autism as well as FXS. Limited human data and several mouse models have implicated the hippocampal dentate gyrus (DG) in autism. We therefore investigated whether the Fmr1-KO mouse exhibited functional changes in DG. We found diminished medial perforant path-granule cell long-term potentiation (LTP), complementing previous investigations of synaptic plasticity in Fmr1-KO demonstrating impaired LTP in CA1, neocortex, and amygdala and exaggerated long-term depression in CA1. We also found that peak amplitude of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) was smaller in Fmr1-KO than control. AMPA receptor-mediated EPSCs were comparable in the two strains, yielding a lower NMDA/AMPA ratio in Fmr1-KO mice and suggesting one mechanism by which absent FMRP might contribute to diminished LTP. The clinical hallmarks of autism include both excessive adherence to patterns and impaired detection of socially important patterns. The DG has a putative role in pattern separation (for time, space, and features) that has been attributed to granule cell number, firing rates, adult neurogenesis, and even perforant path LTP. DG also contributes to pattern completion in CA3 via its mossy fiber efferents, whose terminals include abundant FMRP in “fragile X granules.” Together with the present data, these observations suggest that DG is a candidate region for further investigation in autism and that the Fmr1-KO model may be particularly apt. © 2010 Wiley-Liss, Inc.

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