Neurotransmitter receptors: Another trick up GABABR's sleeve
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Metabotropic GABA (γ-aminobutyric acid) type B receptors (GABA B Rs) play an important part in the regulation of synaptic transmission as they inhibit presynaptic release and activate postsynaptic K + channels. Now, Chalifoux and Carter show that GABA B Rs also suppress postsynaptic Ca 2+ signals mediated by NMDARs (N-methyl-d-aspartate receptors) and inhibit multivesicular release at individual spines. The authors used two-photon optical quantal analysis to study synaptic transmission at individual spines on the dendrites of layer 2–3 pyramidal neurons from acute prefrontal cortical slices. They found that the GABA B R agonist baclofen decreased both the probability of release and the synaptic potency (the amplitude of successful release events). Inhibiting signalling down- stream of postsynaptic GABA B Rs with the non-hydrolysable GDP analogue guanosine-5′-(β-thio) diphosphate (GDP-βS) did not pre- vent the decrease in synaptic potency. As this effect of baclofen was no longer evident under conditions of low extracellular Ca 2+ concentration, these results suggest that GABA B R signalling regulates multivesicular release at the presynaptic terminal. To study the effects of GABA B R activation on postsynaptic NMDAR- dependent Ca 2+ signals, the authors used two-photon glutamate uncag- ing. GDP-βS prevented the inhibition of NMDAR-dependent Ca 2+ signals by baclofen in individual spines, showing that modulation of the postsynaptic Ca 2+ signal by GABA B R requires G protein activation. Similar results were obtained using the protein kinase A (PKA) antagonist H89 and the PKA-inhibiting peptide PKI, implicating the PKA pathway in the postsynaptic effects of GABA B R activation. Finally, GABA B R activa- tion had no effect on overall synaptic currents mediated either by NMDAR or AMPA (α-amino-3-hydroxyl- 5-methyl-4-isoxazole-propionate) receptors. Together, these results suggest that GABA B Rs selectively regulate the Ca 2+ permeability of NMDARs. By taking advantage of a combination of optical tools, this study identifies novel presynaptic and postsynaptic mechanisms by which GABA B Rs influence synaptic transmission at individual spines. As NMDAR-dependent Ca 2+ signals in neuronal spines are particularly important for synaptic plasticity and spine excitability, their regulation by GABA B Rs is likely to have wide implications for our understanding of neuronal physiology. Cristian Bodo ORIGINAL RESEARCH PAPER Chalifoux, J. R. & Carter, A. G. GABA B receptors modulate NMDA receptor calcium signals in dendritic spines. Neuron 66, 101–113 (2010) NEUROTRANSMITTER RECEPTORS Another trick up GABA B R’s sleeve RESEARCH HIGHLIGHTS NATURE REVIEWS | NEUROSCIENCE VOLUME 11 | JUNE 2010 Nature Reviews Neuroscience | AOP, published online 12 May 2010; doi:10.1038/nrn2857 © 20 Macmillan Publishers Limited. All rights reserved 10
Transcript of Neurotransmitter receptors: Another trick up GABABR's sleeve
Metabotropic GABA (γ-aminobutyric acid) type B receptors (GABABRs) play an important part in the regulation of synaptic transmission as they inhibit presynaptic release and activate postsynaptic K+ channels. Now, Chalifoux and Carter show that GABABRs also suppress postsynaptic Ca2+ signals mediated by NMDARs (N-methyl-d-aspartate receptors) and inhibit multivesicular release at individual spines.
The authors used two-photon optical quantal analysis to study synaptic transmission at individual
spines on the dendrites of layer 2–3 pyramidal neurons from acute prefrontal cortical slices. They found that the GABABR agonist baclofen decreased both the probability of release and the synaptic potency (the amplitude of successful release events). Inhibiting signalling down-stream of postsynaptic GABABRs with the non-hydrolysable GDP analogue guanosine-5′-(β-thio)diphosphate (GDP-βS) did not pre-vent the decrease in synaptic potency. As this effect of baclofen was no longer evident under conditions of low extracellular Ca2+ concentration, these results suggest that GABABR signalling regulates multivesicular release at the presynaptic terminal.
To study the effects of GABABR activation on postsynaptic NMDAR-dependent Ca2+ signals, the authors used two-photon glutamate uncag-ing. GDP-βS prevented the inhibition of NMDAR-dependent Ca2+ signals by baclofen in individual spines, showing that modulation of the postsynaptic Ca2+ signal by GABABR requires G protein activation. Similar results were obtained using the protein kinase A (PKA) antagonist
H89 and the PKA-inhibiting peptide PKI, implicating the PKA pathway in the postsynaptic effects of GABABR activation. Finally, GABABR activa-tion had no effect on overall synaptic currents mediated either by NMDAR or AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) receptors. Together, these results suggest that GABABRs selectively regulate the Ca2+ permeability of NMDARs.
By taking advantage of a combination of optical tools, this study identifies novel presynaptic and postsynaptic mechanisms by which GABABRs influence synaptic transmission at individual spines. As NMDAR-dependent Ca2+ signals in neuronal spines are particularly important for synaptic plasticity and spine excitability, their regulation by GABABRs is likely to have wide implications for our understanding of neuronal physiology.
Cristian Bodo
ORIGINAL RESEARCH PAPER Chalifoux, J. R. & Carter, A. G. GABA
B receptors modulate NMDA
receptor calcium signals in dendritic spines. Neuron 66, 101–113 (2010)
N E u R Ot R A N S m I t t E R R E C E P tO R S
Another trick up GABABR’s sleeve
R e s e a R c h h i g h l i g h t s
NATuRe RevIewS | NeuroscieNce voluMe 11 | juNe 2010
Nature Reviews Neuroscience | AoP, published online 12 May 2010; doi:10.1038/nrn2857
© 20 Macmillan Publishers Limited. All rights reserved10
