title: Forebrain-specific loss of synaptic GABAA receptors results in altered neuronal excitability and synaptic plasticity in mice.
abstract: Mutations that result in the defective trafficking of γ2 subunit containing GABAA receptors (γ2-GABAARs) are known to reduce synaptic inhibition. Whether perturbed clustering of non-mutated GABAARs similarly reduces synaptic inhibition in vivo is less clear. In this study we provide evidence that the loss of postsynaptic γ2-GABAARs upon postnatal ablation of gephyrin, the major scaffolding protein of inhibitory postsynapses, from mature principal neurons within the forebrain results in reduced induction of long-term potentiation (LTP) and impaired network excitability within the hippocampal dentate gyrus. The preferential reduction in not only synaptic γ2-GABAAR cluster number at dendritic sites but also the decrease in γ2-GABAAR density within individual clusters at dendritic inhibitory synapses suggests that distal synapses are more sensitive to the loss of gephyrin expression than proximal synapses. The fact that these mice display behavioural features of anxiety and epilepsy emphasises the importance of postsynaptic γ2-GABAAR clustering for synaptic inhibition.
authors.affiliation: Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60318 Frankfurt/Main, Germany; Max-Planck-Institute of Cell Biology & Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. Electronic address: gregory.a.osullivan@gmail.com.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: O'Sullivan
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, 60590 Frankfurt/Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60318 Frankfurt/Main, Germany.
authors.forename: Hong-Xing
authors.initials: HX
authors.lastname: Chen
authors.affiliation: Institute of Anatomy & Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
authors.forename: Heba
authors.initials: H
authors.lastname: Kalbouneh
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, 60590 Frankfurt/Main, Germany.
authors.forename: Angelo
authors.initials: A
authors.lastname: Ippolito
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, 60590 Frankfurt/Main, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Deller
authors.affiliation: Institute of Anatomy & Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Nawrotzki
authors.affiliation: Institute of Anatomy & Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Kuhse
authors.affiliation: Max-Planck-Institute of Cell Biology & Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
authors.forename: Yannis L
authors.initials: YL
authors.lastname: Kalaidzidis
authors.affiliation: Institute of Anatomy & Cell Biology, University of Heidelberg, Im Neuenheimer Feld 307, 69120 Heidelberg, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kirsch
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University, 60590 Frankfurt/Main, Germany.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Schwarzacher
authors.affiliation: Department of Neurochemistry, Max-Planck-Institute for Brain Research, Deutschordenstrasse 46, 60318 Frankfurt/Main, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Betz
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018891:Dentate Gyrus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D017774:Long-Term Potentiation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D055366:Synaptic Potentials
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011963:Receptors, GABA-A; C073441:gephyrin
keywords: epilepsy; gephyrin; inhibitory synapse; mouse knockout; γ2-GABA(A)Rs