Compartmentalization of the GABA<sub>B</sub>Receptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

Laviv, Tal; Vertkin, Irena; Berdichevsky, Yevgeny; Fogel, Hilla; Riven, Inbal; Bettler, Bernhard; Slesinger, Paul A.; Slutsky, Inna

doi:10.1523/jneurosci.1527-11.2011

Cited by 43 publications

(37 citation statements)

References 62 publications

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“…Moreover, coactivation of presynaptic GABA B R at the transgenic excitatory synapses may curtail glutamate release itself, thus further decreasing the possiblity of facilitation (55). In fact, this regulatory action of presynaptic GABA B R is well-documented for many excitatory and inhibitory synapses (55)(56)(57)(58)(59)(60), suggesting that recruitment of (additional) presynaptic GABA B R triggered by our ectopic expression of Nxph1 may again only enhance a natural process. Finally, in both mouse models and types of synapses investigated, evoked release (eIPSC in NRT and eEPSC in neocortex) was unchanged over a range of stimulation strengths, suggesting that the efficiency of .…”

Section: Discussionmentioning

confidence: 97%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like α-neurexins (α-Nrxn) and their extracellular binding partners determine synapse function. Although α-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an α-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABA B receptor (GABA B R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA B R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA B R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA B R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA A R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA B R and postsynaptic GABA A R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA A R and GABA B R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. synaptic transmission | thalamus | autism | neuroligin | ultrastructure

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Section: Discussionmentioning

confidence: 97%

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Born

Breuer

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…GB 1a WT-, GB 1a ΔPCT-, GB 2 -, and Ca V 2.2-tagged proteins used throughout the study were constructed as described before (30). Synt 1a (CSYS-5RK), Synt 1a Open , and Synt 1a K253I are as described in ref.…”

Section: Methodsmentioning

confidence: 99%

“…Intensity-based FRET imaging was carried as described before (22,30). Donor dequenching resulting from the desensitized acceptor was measured from Cer/CFP emission (460-500 nm) before and after the acceptor (YFP) photobleaching.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous work, we identified the proximal C-terminal domain of the GB 1a protein (R857-S877; GB 1a PCT; Fig. 6A) as essential for the compartmentalization of the presynaptic signaling complex of GABA B Rs, Gβγ G protein subunits, and Ca V 2.2 channels in hippocampal boutons (30). Interestingly, deletion of GB 1a PCT domain specifically impaired Ca V 2.2/Gβγ interaction and function, leaving Gα i/o -dependent signaling unaltered.…”

Section: Gb 1a Is Required For Homeostatic Increase In Presynaptic Camentioning

confidence: 99%

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GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Vertkin

Styr

Slomowitz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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 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.homeostatic plasticity | GABA B receptor | synaptic vesicle release | syntaxin-1 | FRET

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“…The rat Ca v 2.2 channel, a 1B splice variant e37a, and auxiliary subunit b 3 were provided by Dr. Diane Lipscombe (Brown University), and the auxiliary subunit a 2 d 1 was provided by Dr. Gerald W. Zamponi (University of Calgary). Rat wild-type GABA B R and the mutant GABA B1a -ΔPCT, GABA B1a -Δ887, GABA B1a -Δ863 (Laviv et al, 2011), and GABA B2 -R576D (Binet et al, 2007;Boyer et al, 2009) constructs have been described previously. Site-directed mutagenesis on GABA B1a was carried out using the GENEART Site-Directed Mutagenesis System Kit (Invitrogen/Life Technologies, Mulgrave, VIC, Australia) with the following primers:…”

Section: Methodsmentioning

confidence: 99%

Novel Mechanism of Voltage-Gated N-type (Ca_v2.2) Calcium Channel Inhibition Revealed through α-Conotoxin Vc1.1 Activation of the GABA_B Receptor

et al. 2014

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Neuronal voltage-gated N-type (Ca v 2.2) calcium channels are expressed throughout the nervous system and regulate neurotransmitter release and hence synaptic transmission. They are predominantly modulated via G protein-coupled receptor activated pathways, and the well characterized Gbg subunits inhibit Ca v 2.2 currents. Analgesic a-conotoxin Vc1.1, a peptide from predatory marine cone snail venom, inhibits Ca v 2.2 channels by activating pertussis toxin-sensitive G i/o proteins via the GABA B receptor (GABA B R) and potently suppresses pain in rat models. Using a heterologous GABA B R expression system, electrophysiology, and mutagenesis, we showed a-conotoxin Vc1.1 modulates Ca v 2.2 via a different pathway from that of the GABA B R agonists GABA and baclofen. In contrast to GABA and baclofen, Vc1.1 changes Ca v 2.2 channel kinetics by increasing the rate of activation and shifting its halfmaximum inactivation to a more hyperpolarized potential. We then systematically truncated the GABA B1a C terminus and discovered that removing the proximal carboxyl terminus of the GABA B1a subunit significantly reduced Vc1.1 inhibition of Ca v 2.2 currents. We propose a novel mechanism by which Vc1.1 activates GABA B R and requires the GABA B1a proximal carboxyl terminus domain to inhibit Ca v 2.2 channels. These findings provide important insights into how GABA B Rs mediate Ca v 2.2 channel inhibition and alter nociceptive transmission.

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Compartmentalization of the GABA_BReceptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

Cited by 43 publications

References 62 publications

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Novel Mechanism of Voltage-Gated N-type (Ca_v2.2) Calcium Channel Inhibition Revealed through α-Conotoxin Vc1.1 Activation of the GABA_B Receptor

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Compartmentalization of the GABABReceptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

Cited by 43 publications

References 62 publications

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

Modulation of synaptic function through the α-neurexin–specific ligand neurexophilin-1

GABA B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Novel Mechanism of Voltage-Gated N-type (Cav2.2) Calcium Channel Inhibition Revealed through α-Conotoxin Vc1.1 Activation of the GABAB Receptor

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Product

Resources

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Compartmentalization of the GABA_BReceptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

GABA _B receptor deficiency causes failure of neuronal homeostasis in hippocampal networks

Novel Mechanism of Voltage-Gated N-type (Ca_v2.2) Calcium Channel Inhibition Revealed through α-Conotoxin Vc1.1 Activation of the GABA_B Receptor