MGluR1‐β‐arrestin 2 Signaling Mediates Induction of Excitatory Synaptic Plasticity

Abstract

A subset of seven‐transmembrane receptors (7TMRs) couple to both G protein‐ and β‐arrestin (βarr)‐mediated signaling pathways. Our objective is to determine if group I metabotropic glutamate receptors (mGluR1 and mGluR5) engage βarr signaling during the induction of synaptic plasticity in the CNS. In these experiments we tested the role of βarr‐Src‐MAPK signaling in the induction of plasticity at the hippocampal mossy fiber‐CA3 synapse.
 We compared mGluR1‐dependent synaptic plasticity in patch clamp recordings from CA3 pyramidal neurons in hippocampal slices prepared from wildtype, βarr 1 and βarr 2 knockout mice. Potentiation of EPSCs induced by low frequency, paired stimulation of mossy fiber inputs to CA3 pyramidal neurons was absent in mice lacking βarr 2 (91 ± 7% n=9 for βarr 2‐/‐, 125 ± 9% n=18 for wildtype, p=0.01) but intact in mice lacking βarr 1 (128 ± 11% n=8 for βarr 1‐/‐, 122 ± 13% n=17 for wildtype, p=0.74). In contrast, high‐frequency stimulation that induced long‐term potentiation was unaffected by gene targeting of either βarr isoform (190 ± 23% n=9 for βarr 1‐/‐, 153 ± 18% n=6 for wildtype, p=0.22; 163 ± 18% n=7 for βarr 2‐/‐, 167 ± 14% n=6 for wildtype, p=0.89). Pharmacological dissection implicated ERK1/2 of the MAPK pathway (104 ± 8% n=6 for u0126‐treated slices, 139 ± 9% n=15 for vehicle slices, p=0.01), whereas the role of Src tyrosine kinases was equivocal (114 ± 8% n=9 for PP2‐treated slices, 139 ± 9% n=15 for vehicle slices, p=0.06). 
 These data reveal a novel signaling function for βarrs when coupled to mGluR1 and therefore yield insight into new strategies for therapeutic targeting of group I mGluRs, which in recent years has been pursued for a number of neuropathologies.
 Research supported by R21 NS088916‐01 from NINDS to GTS.