Another trick up GABA_BR's sleeve

Metabotropic GABA (γ-aminobutyric acid) type B receptors (GABA_BRs) 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_BRs 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 GABA_BR agonist baclofen decreased both the probability of release and the synaptic potency (the amplitude of successful release events). Inhibiting signalling downstream of postsynaptic GABA_BRs with the non-hydrolysable GDP analogue guanosine-5′-(β-thio)diphosphate (GDP-βS) did not prevent 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 GABA_BR signalling regulates multivesicular release at the presynaptic terminal.

To study the effects of GABA_BR activation on postsynaptic NMDAR-dependent Ca²⁺ signals, the authors used two-photon glutamate uncaging. GDP-βS prevented the inhibition of NMDAR-dependent Ca²⁺ signals by baclofen in individual spines, showing that modulation of the postsynaptic Ca²⁺ signal by GABA_BR 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_BR activation. Finally, GABA_BR activation 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_BRs 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 GABA_BRs 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 GABA_BRs is likely to have wide implications for our understanding of neuronal physiology.