Transduction of group I mGluR-mediated synaptic plasticity by β-arrestin2 signalling

Conventional signalling by the group I metabotropic glutamate receptors, mGluR1 and mGluR5, occurs through G-protein coupling, but evidence suggests they might also utilize other, non-canonical effector pathways. Here we test whether group I mGluRs require beta-arrestin signalling during specific forms of plasticity at hippocampal excitatory synapses. We find that genetic ablation of beta-arrestin2, but not beta-arrestin1, results in deficits in plasticity mediated by mGlu1 receptors in CA3 pyramidal neurons and by mGlu5 receptors in CA1 pyramidal neurons. Pharmacological studies additionally support roles for Src kinases and MAPK/ERK downstream of beta-arrestin2 in CA3 neurons. mGluR1 modulation of intrinsic conductances is otherwise preserved in beta-arrestin2(-/-) mice with the exception of a rebound depolarization, and non-mGluR-mediated long-term potentiation is unaltered. These results reveal a signalling pathway engaged by group I mGluRs to effect changes in synaptic and cell intrinsic physiology dependent upon beta-arrestin rather than G proteins. Pharmacological manipulation of mGluRs with effector-biased ligands could lead to novel therapies to treat neurological disease.