Presynaptic long-term depression mediated by Gi/o-coupled receptors

• There are two types of LTD (‘labile’ and ‘static’) that depend upon different receptor dynamics, presynaptic environment, and neurotransmitter tone.
• There is now substantial evidence that presynaptic Gi/o-GPCRs induce presynaptic LTD.
• Activation of presynaptic Gi/o-GPCRs ultimately results in reduced neurotransmitter release probability.
• Interactions between presynaptic Gi/o-GPCRs on the same presynaptic terminal may offer manifold control of neurotransmission.

Long-term depression (LTD) of the efficacy of synaptic transmission is now recognized as an important mechanism for the regulation of information storage and the control of actions, as well as for synapse, neuron, and circuit development. Studies of LTD mechanisms have focused mainly on postsynaptic AMPA-type glutamate receptor trafficking. However, the focus has now expanded to include presynaptically expressed plasticity, the predominant form being initiated by presynaptically expressed Gi/o-coupled metabotropic receptor (Gi/o-GPCR) activation. Several forms of LTD involving activation of different presynaptic Gi/o-GPCRs as a ‘common pathway’ are described. We review here the literature on presynaptic Gi/o-GPCR-mediated LTD, discuss known mechanisms, gaps in our knowledge, and evaluate whether all Gi/o-GPCRs are capable of inducing presynaptic LTD.