The delta family of
ionotropic glutamate receptors consists of
glutamate delta-1 (GluD1) and
glutamate delta-2 receptors. We have previously shown that GluD1 knockout mice exhibit features of developmental delay, including impaired spine pruning and switch in the
N-methyl-D-aspartate receptor subunit, which are relevant to
autism and other
neurodevelopmental disorders. Here, we identified a novel role of GluD1 in regulating
metabotropic glutamate receptor 5 (mGlu5) signaling in the hippocampus. Immunohistochemical analysis demonstrated colocalization of mGlu5 with GluD1 punctas in the hippocampus. Additionally, GluD1
protein coimmunoprecipitated with mGlu5 in the hippocampal membrane fraction, as well as when overexpressed in human embryonic kidney 293 cells, demonstrating that GluD1 and mGlu5 may cooperate in a signaling complex. The interaction of mGlu5 with scaffold
protein effector Homer, which regulates mechanistic target of
rapamycin (mTOR) signaling, was abnormal both under basal conditions and in response to mGlu1/5 agonist (RS)-3,5-dihydroxyphenylglycine (
DHPG) in GluD1 knockout mice. The basal levels of phosphorylated mTOR and
protein kinase B, the signaling
proteins downstream of mGlu5 activation, were higher in GluD1 knockout mice, 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor subunits was impaired in the GluD1 knockout mice. These results demonstrate that GluD1 interacts 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.