title: Homeostatic competition between phasic and tonic inhibition.
abstract: The GABAA receptors are the major inhibitory receptors in the brain and are localized at both synaptic and extrasynaptic membranes. Synaptic GABAA receptors mediate phasic inhibition, whereas extrasynaptic GABAA receptors mediate tonic inhibition. Both phasic and tonic inhibitions regulate neuronal activity, but whether they regulate each other is not very clear. Here, we investigated the functional interaction between synaptic and extrasynaptic GABAA receptors through various molecular manipulations. Overexpression of extrasynaptic α6β3δ-GABAA receptors in mouse hippocampal pyramidal neurons significantly increased tonic currents. Surprisingly, the increase of tonic inhibition was accompanied by a dramatic reduction of the phasic inhibition, suggesting a possible homeostatic regulation of the total inhibition. Overexpressing the α6 subunit alone induced an up-regulation of δ subunit expression and suppressed phasic inhibition similar to overexpressing the α6β3δ subunits. Interestingly, blocking all GABAA receptors after overexpressing α6β3δ receptors could not restore the synaptic GABAergic transmission, suggesting that receptor activation is not required for the homeostatic interplay. Furthermore, insertion of a gephyrin-binding-site (GBS) into the α6 and δ subunits recruited α6(GBS)β3δ(GBS) receptors to postsynaptic sites but failed to rescue synaptic GABAergic transmission. Thus, it is not the positional effect of extrasynaptic α6β3δ receptors that causes the down-regulation of phasic inhibition. Overexpressing α5β3γ2 subunits similarly reduced synaptic GABAergic transmission. We propose a working model that both synaptic and extrasynaptic GABAA receptors may compete for limited receptor slots on the plasma membrane to maintain a homeostatic range of the total inhibition.
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
authors.forename: Xia
authors.initials: X
authors.lastname: Wu
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and; the Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Lanting
authors.initials: L
authors.lastname: Huang
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
authors.forename: Ce
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
authors.forename: Dongyun
authors.initials: D
authors.lastname: Jiang
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Bai
authors.affiliation: the Institutes of Brain Science and State Key Laboratory for Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Biology, The Huck Institutes of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802 and. Electronic address: gongchen@psu.edu.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013570:Synaptic Membranes / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D011963:Receptors, GABA-A
keywords: GABA Receptors; Neurobiology; Neurons; Neurotransmitter Release; Synapses