GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-06, Vol.112 (25), p.E3291-E3299
• Main Authors: Vertkin, Irena, Boaz Styr, Edden Slomowitz, Nir Ofir, Ilana Shapira, David Berner, Tatiana Fedorova, Tal Laviv, Noa Barak-Broner, Dafna Greitzer-Antes, Martin Gassmann, Bernhard Bettler, Ilana Lotan, Inna Slutsky
• Format: Article
• Language: English
• Subjects: Animals; behavior disorders; Biological Sciences; brain; Cells, Cultured; epilepsy; Evoked Potentials; FRET; GABAB receptor; gamma-aminobutyric acid; Hippocampus - cytology; Hippocampus - physiology; Homeostasis; homeostatic plasticity; Mice; Mice, Inbred BALB C; Neurons - metabolism; neurophysiology; PNAS Plus; receptors; Receptors, GABA-B - metabolism; synaptic vesicle release; syntaxin-1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1424810112

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 GABA B, but not GABA A, receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA B receptor (GABA BR) blockade or genetic deletion of the GB ₁ₐ receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA BRs 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 V2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB ₁b-containing receptors. Thus, GABA BRs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA BR 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 BRs. Significance How neuronal circuits maintain stable activity despite continuous environmental changes is one of the most intriguing questions in neuroscience. Previous studies proposed that deficits in homeostatic control systems may underlie common neurological symptoms in a variety of brain disorders. However, the key regulatory molecules that control homeostasis of central neural circuits remain obscure. We show here that basal activity of GABA B receptors is required for firing rate homeostasis in hippocampal networks. We identified t