Impaired social behaviors and minimized oxytocin signaling of the adult mice deficient in the N-methyl-d-aspartate receptor GluN3A subunit

Abstract

The N-methyl-d-aspartate receptor (NMDAR) has been implicated in the pathophysiology of neurological diseases, such as schizophrenia, autism spectrum disorders (ASD), and Alzheimer's disease (AD), whose unique clinical hallmark is a constellation of impaired social and/or cognitive behaviors. GluN3A (NR3A) is a unique inhibitory subunit in the NMDAR complex. The role of GluN3A in social behavioral activities is obscure. In this study, we sought to evaluate altered social activities in adult GluN3A knockout (KO) mice. GluN3A KO mice spent less time in reciprocal social interaction in the social interaction test compared to wild-type (WT) mice. A social approach test using a three-chamber system confirmed that mice lacking GluN3A had lower sociability and did not exhibit a preference for social novelty. GluN3A KO mice displayed abnormal food preference in the social transmission of food preference task and low social interaction activity in the five-trial social memory test, but without social memory deficits. Using a home cage monitoring system, we observed reduced social grooming behavior in GluN3A KO mice. Signaling genes that might mediate the altered social behaviors were examined in the prefrontal cortex, hippocampus, and thalamus. Among nine genes examined, the expression of the oxytocin receptor was significantly lower in the prefrontal cortex of GluN3A KO mice than that in WT mice. Oxytocin treatment rescued social activity deficits in GluN3A KO mice. These findings support a novel idea that a chronic state of moderate increases in NMDAR activities may lead to downregulation of the oxytocin signaling and impaired behavioral activities that are seen in psychiatric/neurodegenerative disorders.

Neuropsychological Deficits Chronically Developed after Focal Ischemic Stroke and Beneficial Effects of Pharmacological Hypothermia in the Mouse

“…Oxytocin is a neuropeptide that acts as a social hormone in the CNS [22]. Administration of oxytocin has been demonstrated to restore social activities in autistic animals and to ameliorate emotional-social deficits associated with post-traumatic stress disorder (PTSD) [62].…”

“…A small stroke model of right sensorimotor cortex ischemia with partial reperfusion in adult mice was tested in this investigation [14,[21][22][23]. The ischemic insult included the permanent occlusion of the distal branch of the right MCA, accompanied with 7-min ligation of the bilateral CCAs.…”

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…Total RNA was extracted from samples using Trizol (Thermo Fisher Scientific) as previously described by Lee et al (34). The RNA samples were reverse transcribed to cDNA in 20 ml of a reaction mixture containing 20-times RT buffer and 20-times RT enzyme mix according to the manufacturer's instruction (Thermo Fisher Scientific) at 37°C for 60 min as previously described by Lee et al (35). The samples were then incubated at 95°C for 5 min and transferred to 4°C.…”

Increase in neuropeptide Y activity impairs social behaviour in association with glutamatergic dysregulation in diabetic mice

“…Interaction time was defined as the time during which the head of the test mouse was within 2 cm from the cage. While behaviour was measured for 10 min in each session, as described previously (Lee, Zhang, Wei, & Yu, 2018; Nakatani et al, 2009), it has been reported that most interactions occur during 0–5 min, with considerably fewer interactions occurring during 5–10 min (Nadler et al, 2004). Therefore, interaction time (%) was calculated as the ratio of interaction time with one cage to total interaction time with both cages during the first 5 min of each session.…”