Social Preference and Glutamatergic Dysfunction: Underappreciated Prerequisites for Social Dysfunction in Schizophrenia

Abstract

Impaired social functioning is pervasive in schizophrenia. Unfortunately, existing treatments have limited efficacy and possible psychological or neurobiological mechanisms underlying social dysfunction in this disorder remain obscure. Here, we evaluate whether social preference, one key aspect of social processing that has been largely overlooked in schizophrenia research, and N-methyl-d-aspartate receptor (NMDAR) dysfunction can provide insights into the mechanism underlying social dysfunction in schizophrenia. Based on evidence from developmental psychology, and behavioral and clinical neuroscience, we propose a heuristic model in which reduced NMDAR function may induce disrupted social preference that can subsequently lead to social cognitive impairment and social disability. We discuss its implications in terms of the pathophysiology of schizophrenia, other disorders with marked social disability, and potential treatments.

Prospective Analysis of the Effects of Maternal Immune Activation on Rat Cytokines during Pregnancy and Behavior of the Male Offspring Relevant to Schizophrenia

“…Illnesses with a neurodevelopmental component like autism and schizophrenia have social deficits as a central feature, which fits with our finding that an early developmental insult impacted this behavior domain. Normal social functioning is dependent on neurodevelopmental processes as shown by the particularly deleterious effects of early life insult ( Lee and Green, 2016 ). Early life deletion of the NR1 subunit, but not postadolescent deletion in mice results in impaired social preference and early childhood prefrontal cortex (PFC) damage in humans is associated with impaired sociability ( Anderson et al, 2000 ).…”

“…The developmental effects of maternal inflammation are broad, and the impairments seen in our study could be related to the impact of developmental immune insult in one or several of these areas. NMDAR hypofunction induced by pharmacologic, genetic, and optogenetic means in mice disrupts preference for a stranger conspecific, and there is prior evidence for NMDAR disruption in MIA offspring as well as structural changes in the brain regions required for typical social proficiency, particularly the PFC ( Samuelsson et al, 2006 ; Piontkewitz et al, 2011b ; Lee and Green, 2016 ).…”

Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

“…We believe comparing treatment groups allows the detection of subtle behavior differences that could be missed in instances where stimuli with a substantial difference in salience (such as an unfamiliar rat vs an empty cage) result in high DRs, and this natural preference would need to be abolished to show a treatment effect. Natural preference for social stimuli versus objects is documented in rodents (Lee and Green, 2016). Presenting the data as a between groups comparison also allows direct evaluation alongside previously published sociability data from our lab, including that of the male littermates from this cohort (Henbid et al, 2017; Lins et al, 2018).…”

Effects of post-weaning social isolation on social behaviors and oxytocinergic activity in male and female rats

“…This result suggests that social isolation reduces the preference for social novelty observed in pair-reared animals. The preferential processing of social over non-social stimuli is commonly observed in healthy adult humans, while it is disrupted in schizophrenia, autism, and the rodent models of these disorders [22, 23, 24]. This bias is thought to result from a difference in reward values between social and non-social stimuli [25, 26].…”