Abstract
The GluD1 gene is associated with susceptibility for schizophrenia, autism, depression, and bipolar disorder. However, the function of GluD1 and how it is involved in these conditions remain elusive. In this study, we generated a Grid1 gene-knockout (GluD1-KO) mouse line with a pure C57BL/6N genetic background and performed several behavioral analyses. Compared to a control group, GluD1-KO mice showed no significant anxiety-related behavioral differences, evaluated using behavior in an open field, elevated plus maze, a light-dark transition test, the resident-intruder test of aggression and sensorimotor gating evaluated by the prepulse inhibition test. However, GluD1-KO mice showed (1) higher locomotor activity in the open field, (2) decreased sociability and social novelty preference in the three-chambered social interaction test, (3) impaired memory in contextual, but not cued fear conditioning tests, and (4) enhanced depressive-like behavior in a forced swim test. Pharmacological studies revealed that enhanced depressive-like behavior in GluD1-KO mice was restored by the serotonin reuptake inhibitors imipramine and fluoxetine, but not the norepinephrine transporter inhibitor desipramine. In addition, biochemical analysis revealed no significant difference in protein expression levels, such as other glutamate receptors in the synaptosome and postsynaptic densities prepared from the frontal cortex and the hippocampus. These results suggest that GluD1 plays critical roles in fear memory, sociability, and depressive-like behavior.
Highlights
The δ-type ionotropic glutamate receptor consists of GluD1 (GluRδ1) and GluD2 (GluRδ2) [1,2,3]
It is well established that performance in both the open field and elevated plus maze are influenced by the arena illumination levels [87,88]
There were no significant differences in the percentage of time spent in the central area between WT and GluD1-KO mice under either illumination conditions (Fig 1C and 1E)
Summary
The δ-type ionotropic glutamate receptor consists of GluD1 (GluRδ1) and GluD2 (GluRδ2) [1,2,3]. Despite having conserved membrane topology and amino acid residues critical for glutamate binding and Ca2+ permeability, the δ subfamily members do not function as conventional glutamate-gated receptor channels when expressed alone or in combinations with other ionotropic glutamate receptor subunits [4,5,6]. Instead, they are components of a tripartite transsynaptic adhesion system, where the extracellular domain of postsynaptic GluD1/2 interacts with that of presynaptic neurexin protein (NRXN) via members of the cerebellin precursor protein (CBLN) family in the synaptic cleft [7,8,9]. GluD2 regulates cerebellar synaptic plasticity [15,17] and motor learning [15,18,19] by interaction with the scaffolding proteins through its carboxyl-terminal domain [20,21,22]
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