title: Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice.
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 GABAAreceptor 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 GABAAreceptor-mediated phasic inhibition. These abnormalities might contribute to the behavioral and cognitive deficits of this fragile X mouse model.
authors.affiliation: Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium. Electronic address: victor.sabanov@kuleuven.be.
authors.forename: Victor
authors.initials: V
authors.lastname: Sabanov
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. Electronic address: sien.braat@gmail.com.
authors.forename: Sien
authors.initials: S
authors.lastname: Braat
authors.affiliation: Center for Human Genetics-VIB Center for the Biology of Disease, KULeuven, Leuven, Belgium; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy. Electronic address: laudandrea@gmail.com.
authors.forename: Laura
authors.initials: L
authors.lastname: D'Andrea
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. Electronic address: r.willemsen@erasmusmc.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. Electronic address: s.zeidler@erasmusmc.nl.
authors.forename: Shimriet
authors.initials: S
authors.lastname: Zeidler
authors.affiliation: Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium. Electronic address: liesbeth.rooms@uantwerpen.be.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Rooms
authors.affiliation: Center for Human Genetics-VIB Center for the Biology of Disease, KULeuven, Leuven, Belgium; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Italy; Department of Fundamental Neuroscience, University of Lausanne, Switzerland. Electronic address: claudia.bagni@cme.vib-kuleuven.be.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium. Electronic address: frank.kooy@uantwerpen.be.
authors.forename: R Frank
authors.initials: RF
authors.lastname: Kooy
authors.affiliation: Laboratory of Biological Psychology, KU Leuven, Leuven, Belgium. Electronic address: detlef.balschun@kuleuven.be.
authors.forename: Detlef
authors.initials: D
authors.lastname: Balschun
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000378:metabolism; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D058787:GABA-A Receptor Antagonists; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C497684:Fmr1 protein, mouse
keywords: Fmr1 knockout mice; Fragile X syndrome; GABA(A) receptor subunit; Hippocampus; Inhibitory postsynaptic current