Abstract
The delta family of ionotropic glutamate receptors consists of glutamate delta-1 (GluD1) and glutamate delta-2 (GluD2) receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in NMDA receptor subunit which are relevant to autism and other neurodevelopmental disorders. Here we have identified a novel role of GluD1 in regulating mGlu5 signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1 protein co-immunoprecipitated with mGlu5 in hippocampal membrane fraction as well as when overexpressed in HEK 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold protein effector Homer which regulates mTOR signaling was abnormal both under basal conditions and in response to mGlu1/5 agonist DHPG in GluD1 knockout mice. The basal levels of phosphorylated mTOR and Akt, the signaling proteins downstream of mGlu5 activation, were higher in GluD1 knockout and no further increase was induced by DHPG. We also observed higher basal protein translation and an absence of DHPG-induced increase in GluD1 knockout mice. In accordance with a role of mGlu5-mediated mTOR signaling in synaptic plasticity, DHPG-induced internalization of surface AMPA receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interact with mGlu5 and loss of GluD1 impairs normal mGlu5 signaling potentially by dysregulating coupling to its effector. These studies identify a novel role of the enigmatic GluD1 subunit in hippocampal function.
- The American Society for Pharmacology and Experimental Therapeutics