title: GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks.
abstract: Stabilization of neuronal activity by homeostatic control systems is fundamental for proper functioning of neural circuits. Failure in neuronal homeostasis has been hypothesized to underlie common pathophysiological mechanisms in a variety of brain disorders. However, the key molecules regulating homeostasis in central mammalian neural circuits remain obscure. Here, we show that selective inactivation of GABAB, but not GABA(A), receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA(B) receptor (GABA(B)R) blockade or genetic deletion of the GB(1a) receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA(B)Rs mediate adaptive presynaptic enhancement to neuronal inactivity by two principle mechanisms: First, neuronal silencing promotes syntaxin-1 switch from a closed to an open conformation to accelerate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and second, it boosts spike-evoked presynaptic calcium flux. In both cases, neuronal inactivity removes tonic block imposed by the presynaptic, GB(1a)-containing receptors on syntaxin-1 opening and calcium entry to enhance probability of vesicle fusion. We identified the GB(1a) intracellular domain essential for the presynaptic homeostatic response by tuning intermolecular interactions among the receptor, syntaxin-1, and the Ca(V)2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB(1b)-containing receptors. Thus, GABA(B)Rs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA(B)R as a key regulator of population firing stability and propose that disruption of homeostatic synaptic plasticity may underlie seizure's persistence in the absence of functional GABA(B)Rs.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Irena
authors.initials: I
authors.lastname: Vertkin
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Boaz
authors.initials: B
authors.lastname: Styr
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Edden
authors.initials: E
authors.lastname: Slomowitz
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Nir
authors.initials: N
authors.lastname: Ofir
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Ilana
authors.initials: I
authors.lastname: Shapira
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Berner
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Tatiana
authors.initials: T
authors.lastname: Fedorova
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Tal
authors.initials: T
authors.lastname: Laviv
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Noa
authors.initials: N
authors.lastname: Barak-Broner
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Dafna
authors.initials: D
authors.lastname: Greitzer-Antes
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Gassmann
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel;
authors.forename: Ilana
authors.initials: I
authors.lastname: Lotan
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 69978 Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel; islutsky@post.tau.ac.il.
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005071:Evoked Potentials; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D006706:Homeostasis; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*
chemical_list: D018080:Receptors, GABA-B
keywords: FRET; GABAB receptor; homeostatic plasticity; synaptic vesicle release; syntaxin-1