Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

NEUROPHARMACOLOGY

卷:116

Article

Sabanov, Victor¹  Braat, Sien²  D'Andrea, Laura^3,4  Willemsen, Rob⁵  Zeidler, Shimriet⁵  Rooms, Liesbeth¹  Bagni, Claudia^3,4,6  Kooy, R. Frank²  Balschun, Detlef¹ 

[1] Katholieke Univ Leuven, Lab Biol Psychol, Tiensestr 102,Box 3714, B-3000 Leuven, Belgium

[2] Univ Antwerp, Dept Med Genet, Antwerp, Belgium

[3] KULeuven, Ctr Human Genet, VIB Ctr Biol Dis, Leuven, Belgium

[4] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy

[5] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands

[6] Univ Lausanne, Dept Fundamental Neurosci, Lausanne, Switzerland

关键词: Fragile X syndrome;    Fmr1 knockout mice;    GABA(A) receptor subunit;    Inhibitory postsynaptic current;    Hippocampus;   

DOI  :  10.1016/j.neuropharm.2016.12.010

来源: Elsevier

【 摘 要 】

Many clinical and molecular features of the fragile X syndrome, a common form of intellectual disability and autism, can be modeled by deletion of the Fmr1 protein (Fmrp) in mice. Previous studies showed a decreased expression of several components of the GABAergic system in Fmr1 knockout mice. Here, we used this mouse model to investigate the functional consequences of Fmrp deletion on hippocampal GABAergic inhibition in the CA1-region of the hippocampus. Whole-cell patch-clamp recordings demonstrated a significantly reduced amplitude of evoked inhibitory postsynaptic currents (eIPSCs) and a decrease in the amplitude and frequency of spontaneous IPSCs. In addition, miniature IPSCs were reduced in amplitude and frequency and decayed significantly slower than mIPSCs in controls. Quantitative real-time PCR revealed a significantly lower expression of alpha 2, beta 1 and delta GABA(A) receptor subunits in the hippocampus of the juvenile mice (P22) compared to wild-type littermates. Correspondingly, we found also at the protein level reduced amounts of alpha 2, beta 1 and delta subunits in Fmr1 knockout mice. Overall, these results demonstrate that the reduction in several components of the GABAergic system is already present at young age and that this reduction results in measurable abnormalities on GABAA receptor mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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