Direct modulation of synaptic vesicle priming by GABAB receptor activation at a glutamatergic synapse

Second messenger cascades involving G proteins(1,2) and calcium(3) are known to modulate neurotransmitter release(4,5). A prominent effect of such a cascade is the downmodulation of presynaptic calcium influx(6,7), which markedly reduces evoked neurotransmitter release(5,7,8). Here we show that G-protein-mediated signalling, such as through GABA (gamma-amino butyric acid) subtype B (GABA(B)) receptors, retards the recruitment of synaptic vesicles during sustained activity and after short-term depression. This retardation occurs through a lowering of cyclic AMP, which blocks the stimulatory effect of increased calcium concentration on vesicle recruitment. In this signalling pathway, cAMP (functioning through the cAMP-dependent guanine nucleotide exchange factor) and calcium/calmodulin cooperate to enhance vesicle priming. The differential modulation of the two forms of synaptic plasticity, presynaptic inhibition and calcium-dependent recovery from synaptic depression, is expected to have interesting consequences for the dynamic behaviour of neural networks.