Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Aberrant Emotional and Social Behaviors

Abstract

The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder.

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

“…We found a deficit in early developmental processes, including dendritic spine pruning and switch in NMDA receptor subunit in GluD1 KO mice (Gupta et al, 2015). In addition, we previously demonstrated that GluD1 KO exhibits social-interaction and reversal-learning deficits and repetitive behaviors which are core features in several neurodevelopmental disorders, in particular autism spectrum disorders (ASDs) (Yadav et al, 2012(Yadav et al, , 2013Gupta et al, 2015). A recent study demonstrated that neurons derived from induce pluripotent stem cells from Rett syndrome patients exhibit an upregulation of GluD1 (Livide et al, 2015).…”

“…The GluD1 KO mice were obtained from Dr. Jian Zuo (St. Jude Children's Hospital, Memphis, TN) (Gao et al, 2007) and maintained as previously described (Yadav et al, 2012) at a constant temperature (22 6 1°C) and a 12-hour light-dark cycle with free access to food and water. Only male mice were used for these studies.…”

“…However, GluN1 subunit ligands, such as D-serine and glycine, bind to the ligandbinding domain and induce conformational change in the GluD1 receptor (Naur et al, 2007;Yadav et al, 2011). We have recently shown that loss of GluD1 in a mouse model leads to abnormal social and emotional behaviors, including social interaction deficits and repetitive behavior (Yadav et al, 2012(Yadav et al, , 2013Gupta et al, 2015). We also observed specific cognitive deficits in hippocampus-dependent contextual fear learning and reversal learning in GluD1 knockout (KO) mice (Yadav et al, 2012(Yadav et al, , 2013.…”

“…GluD1 is widely expressed in the brain, with high levels in the hippocampus (Lomeli et al, 1993;Yadav et al, 2012;Hepp et al, 2014;Konno et al, 2014;Gupta et al, 2015). Among the ionotropic glutamate receptors, delta receptors are unique in that they do not exhibit agonist-induced current in a heterologous expression system.…”

“…We have recently shown that loss of GluD1 in a mouse model leads to abnormal social and emotional behaviors, including social interaction deficits and repetitive behavior (Yadav et al, 2012(Yadav et al, , 2013Gupta et al, 2015). We also observed specific cognitive deficits in hippocampus-dependent contextual fear learning and reversal learning in GluD1 knockout (KO) mice (Yadav et al, 2012(Yadav et al, , 2013. More recently, we have found that loss of GluD1 produces molecular phenotypes relevant to autism and developmental delay, including impaired dendritic spine pruning and switch in N-methyl-D-aspartate (NMDA) receptor GluN2B to the GluN2A subunit in the hippocampus and prefrontal cortex (Grossman et al, 2006;Penzes et al, 2011;Swanger et al, 2011;Gupta et al, 2015).…”