Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

Abstract

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 a-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.

GluD1 knockout mice with a pure C57BL/6N background show impaired fear memory, social interaction, and enhanced depressive-like behavior

“…Similar to GluD2, postsynaptic GluD1 is required for synapse formation and maintenance in vitro via CBLN1/CBLN2/CBLN4 and presynaptic NRXN [7,9,[34][35][36][37]. In addition, GluD1 regulates group 1 mGluRs-mediated long-term depression in the hippocampus ex vivo [38]. Furthermore, activation of group 1 mGluRs trigger the opening of GluD1 channels, which are key determinants of the slow excitatory postsynaptic current ex vivo [12].…”

Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens

“…3 ). In contrast, in the hippocampal CA1 region chemical DHPG-LTD was impaired 20 . However, due to the differences in methodology to detect AMPA receptor-mediated depression (surface biotinylation versus electrophysiology) it is possible that the effect on trafficking of extrasynaptic and synaptic receptors may underlie these differences.…”

“…3a, b ) in GluD1 KO. We have recently shown that GluD1 KO mice exhibit changes in mGluR1/5 signaling 20 , a pathway associated with reward behavior 36 , 37 . Thus, we further tested whether mGluR1/5 agonist DHPG-induced LTD was affected in the MSNs.…”

“…2 ). Because GluDs govern AMPA receptor trafficking 20 , 46 , 47 , it is possible that loss of GluD1 may modulate the normal AMPA receptor trafficking and impair generation of silent synapses. Further molecular studies are necessary to fully understand the role of GluD1 in drug-induced generation of silent synapses.…”

“…Instead the glutamate delta receptors are endowed with the ability to form and maintain synapses by forming a trans -synaptic bridge involving presynaptic partner Neurexin and the mediator molecule Cbln1 18 , 19 . In addition, GluD1 is critical for regulation of postsynaptic signaling 20 . Recently, we have demonstrated that GluD1 modulates dendritic spine-regulating cofilin signaling.…”