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

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.

Ultrastructural localization of glutamate delta 1 (GluD1) receptor immunoreactivity in the mouse and monkey striatum

“…Altered GluD1 expression was also found in neurons derived from patients with Rett syndrome and in a mouse model of Rett syndrome (Livide et al, 2015;Patriarchi et al, 2016). In line with these human data, recent evidence indicates that deletion of GluD1 leads to deficits in fear conditioning, aberrant emotional and social behaviors and depressive-like behaviors in mice (Benamer et al, 2018;Nakamoto, Kawamura, et al, 2020;Yadav et al, 2012;Yadav et al, 2013).…”

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…Studies with GluD1 KO mice have consistently found increased dendritic spine density in hippocampus and prefrontal cortex along with reduced expression of GluA1 and GluN2B (Yadav et al, 2012(Yadav et al, , 2013Gupta et al, 2015). GluD1 KO mice show higher spontaneous activity, lower anxiety-like behavior, increased aggressiveness, reduced social interaction, deficits in learning, and altered cocaine-conditioned place preference (Yadav et al, 2012;Liu et al, 2018;Gantz et al, 2020;Nakamoto et al, 2020a). GluD1-dependent currents have been reported in raphe neurons in response to noradrenergic synaptic input, although the activating mechanism has not been elucidated (Gantz et al, 2020).…”

Probing the ionotropic activity of glutamate GluD2 receptor in HEK cells with genetically-engineered photopharmacology

“…Cbln1 notably binds both the N-terminal domain of postsynaptic GluD2 and presynaptic neurexins, leading to a trans-synaptic bridge that promotes synaptogenesis and is essential for GluD2 signaling in vivo ( Elegheert et al, 2016 ; Suzuki et al, 2020 ). Deletion of genes coding for GluD1 or GluD2 in mouse results in marked behavioral alterations ( Yadav et al, 2012 ; Lalouette et al, 2001 ; Yadav et al, 2013 ; Nakamoto et al, 2020a ), and mutations in these genes in humans have been associated with neurodevelopmental and psychiatric diseases ( Griswold et al, 2012 ; Treutlein et al, 2009 ; Greenwood et al, 2011 ; Cristino, 2019 ), attesting to their functional importance in brain circuits.…”