Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice

Neuropharmacology. 2017 Apr;116:71-81. doi: 10.1016/j.neuropharm.2016.12.010. Epub 2016 Dec 21.

Abstract

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 α2, β1 and δ GABAA 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 α2, β1 and δ 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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / metabolism*
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / metabolism
  • GABA-A Receptor Antagonists / pharmacology
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Miniature Postsynaptic Potentials / drug effects
  • Miniature Postsynaptic Potentials / physiology
  • Patch-Clamp Techniques
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism*
  • RNA, Messenger / metabolism
  • Receptors, GABA-A / metabolism*
  • Tissue Culture Techniques
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Fmr1 protein, mouse
  • GABA-A Receptor Antagonists
  • RNA, Messenger
  • Receptors, GABA-A
  • Fragile X Mental Retardation Protein
  • gamma-Aminobutyric Acid