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.

Keywords: NMDAR hypofunction; schizophrenia; social functioning; social preference.

Figure 1

A) The Y axis represents threat ratio index, in which values greater than 1 indicate faster detection for threat-related stimuli than non-threat-related stimuli. When detecting threat-related stimuli, healthy controls showed a higher threat ratio index for social stimuli than nonsocial stimuli. However, schizophrenia patients showed similar levels of threat ratio index across nonsocial and social stimuli (adapted from [29]). B) Bar graphs show the amount of time a test mouse (either NR1-knockdown mice or wild-type mice treated with MK801) spent around a strange mouse versus a nonsocial stimuli on a three-chamber task over a 10-minute period. The NR1-knockdown mice spent less time around a strange mouse compared to wild type mice (left panel). Similarly, mice treated with NMDAR antagonist, MK801, spent less time around a strange mouse compared to mice treated with saline (right panel). (** p < .005, Student t test) (Adapted from [57]).

Figure 2

In this heuristic model for social disability in schizophrenia (parts depicted in brown), reduced N-methyl-d-aspartate receptor (NMDAR) function leads to disrupted social preference, which in turn leads to diminished social interaction. In this model, diminished social interaction hinders effective development of social cognitive skills in individuals with schizophrenia, ultimately leading to social disability. The effect of disrupted social preference on social cognitive skills and social interaction is hypothesized to start early in life and continues in an interactive fashion throughout the life span. Previous studies suggested that reduced NMDAR function might influence social disability through negative symptoms and through impaired early sensory processing (parts depicted in green).