Trends in Neurosciences
Volume 39, Issue 9, September 2016, Pages 587-596
Journal home page for Trends in Neurosciences

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

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Trends

Impaired social functioning is pervasive in schizophrenia; unfortunately, existing pharmacological or psychological treatments have only limited efficacy in improving social dysfunction.

Little is known about psychological or neurobiological mechanisms underlying social dysfunction in schizophrenia.

Social preference – the tendency to prioritize processing of social over nonsocial stimuli – represents a fundamental way that human beings process social stimuli and is crucial for the development of social cognitive skills and efficient social functioning.

Emerging evidence strongly suggest that social preference is disrupted in schizophrenia.

Mounting evidence from animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction is closely related to disrupted social preference. NMDAR hypofunction is also a key neurobiological component of one of leading pathophysiological theories of schizophrenia.

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.

Section snippets

Context

Impaired social functioning is pervasive in schizophrenia. Individuals with schizophrenia have difficulty sustaining relationships with family members and friends, and have trouble interacting with colleagues in work settings and acquaintances in leisure settings (Box 1). Unfortunately, existing pharmacological or psychological interventions have seen only limited efficacy in improving social dysfunction. Further, pathways for the development of novel treatments are not obvious, as little is

Social Preference: The Way Humans Process Social Stimuli

Human beings are intrinsically tuned for social stimuli in that we prefer social over nonsocial stimuli. The term social preference refers to this bias or tendency to prioritize processing of social over nonsocial stimuli.

Preferential processing of social stimuli can be easily observed during adulthood. For example, healthy adults identify social stimuli much faster than nonsocial stimuli 1, 2 and have more difficulty disengaging from irrelevant social stimuli than from irrelevant nonsocial

Social Preference and Schizophrenia

As shown above, social preference is present across the entire lifespan, from early stages of development throughout adulthood. However, emerging evidence suggests that social preference is disrupted in schizophrenia. When performing attention or memory tasks, schizophrenia patients do not prioritize social stimuli. For example, whereas healthy controls identified social stimuli better than nonsocial stimuli, schizophrenia patients did not show this benefit 23, 24. Healthy controls were able to

Neurobiological Mechanisms of Disrupted Social Preference

One of the prominent theories of the pathophysiology of schizophrenia is NMDAR hypofunction 43, 44. This theory stems from clinical observations of healthy people who experience psychotic symptoms and negative symptoms after taking NMDAR antagonists such as phencyclidine (PCP) or ketamine. Briefly, this theory posits that NMDAR hypofunction leads to a disruption of the γ-aminobutryic acid (GABA) system that usually inhibits pyramidal cells, resulting in excessive release of glutamate and

Disrupted Social Preference, NMDAR Hypofunction, and Social Dysfunction in Schizophrenia

As already shown, social preference is a fundamental way that humans process social information, and this distinction between social and nonsocial stimuli occurs very early in life. What are the implications of social preference for social functioning? Prioritizing social stimuli increases the opportunity to perceive and experience social stimuli and to respond appropriately, thereby facilitating the development of social cognitive skills and resulting in efficient social behaviors. Along these

Concluding Remarks

We evaluated whether social preference, a key aspect of social processing that has been largely overlooked in schizophrenia research, and NMDAR dysfunction could provide insight into potential mechanisms underlying social dysfunction in schizophrenia. Based on available evidence in developmental neuroscience, behavioral neuroscience, and clinical science, we proposed a heuristic model in which reduced NMDAR function in schizophrenia is associated with disrupted social preference, and this

Acknowledgments

The authors wish to thank Jonathan K. Wynn and Gerhard S. Hellemann for helpful comments on an earlier version of the draft. This work is supported by MH102567 (JL), Brain & Behavior Research Foundation NARSAD Young Investigator Award (JL) and MH087618 (MFG). Dr. Lee does not have any conflict of interest. Dr. Green has served as a consultant for AbbVie, ACADIA, DSP, Forum, and Takeda, been on a scientific board for Luc, and received research support from Amgen and Forum.

Glossary

Agonist
a chemical that activates a receptor to initiate biological processes after binding to it.
Antagonist
a chemical that blocks the activation of a receptor after binding to it.
Event-related potentials
a noninvasive brain imaging method that uses electroencephalography to assess electrophysiological responses of a brain to a specific sensory, cognitive, or motor event.
γ-Aminobutryic acid (GABA)
an inhibitory neurotransmitter in the brain that is involved in reducing neuronal excitability.

References (99)

  • V.S. Catts

    A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?

    Biol. Psychol.

    (2016)
  • A. Anticevic

    N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia

    Biol. Psychiatry

    (2015)
  • V.M. Tatard-Leitman

    Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability

    Biol. Psychiatry

    (2015)
  • D.P. Kennedy et al.

    The social brain in psychiatric and neurological disorders

    Trends Cogn. Sci.

    (2012)
  • D.A. Stanley et al.

    Toward a neural basis for social behavior

    Neuron

    (2013)
  • R. Brooks et al.

    Connecting the dots from infancy to childhood: a longitudinal study connecting gaze following, language, and explicit theory of mind

    J. Exp. Child Psychol.

    (2015)
  • T. Tsuji

    Premorbid teacher-rated social functioning predicts adult schizophrenia-spectrum disorder: A high-risk prospective investigation

    Schizophr. Res.

    (2013)
  • S.L. Matheson

    Systematic meta-analysis of childhood social withdrawal in schizophrenia, and comparison with data from at-risk children aged 9-14 years

    J. Psychiatr. Res.

    (2013)
  • M.C. Bertrand

    Social cognitive impairments in first episode psychosis

    Schizophr. Res.

    (2007)
  • P. Roux

    Is the Theory of Mind deficit observed in visual paradigms in schizophrenia explained by an impaired attention toward gaze orientation?

    Schizophr. Res.

    (2014)
  • S. Wang

    Atypical visual saliency in autism spectrum disorder quantified through model-based eye tracking

    Neuron

    (2015)
  • R.H. Tobe

    Differential profiles in auditory social cognition deficits between adults with autism and schizophrenia spectrum disorders: A preliminary analysis

    J. Psychiatr. Res.

    (2016)
  • K. Xu

    Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia

    J. Psychiatr. Res.

    (2015)
  • G.P. Strauss

    Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome

    J. Psychiatr. Res.

    (2013)
  • J.K. Wynn

    Mismatch negativity, social cognition, and functioning in schizophrenia patients

    Biol. Psychiatry

    (2010)
  • S. Dragt

    Environmental factors and social adjustment as predictors of a first psychosis in subjects at ultra high risk

    Schizophr. Res.

    (2011)
  • H. Tibboel

    Is the emotional modulation of the attentional blink driven by response bias?

    Cogn. Emot.

    (2011)
  • S.R. Langton

    Attention capture by faces

    Cognition

    (2012)
  • C. Devue

    Oculomotor guidance and capture by irrelevant faces

    PLoS ONE

    (2012)
  • E.A. Heerey

    Learning from social rewards predicts individual differences in self-reported social ability

    J. Exp. Psychol. Gen.

    (2014)
  • M. Colombo

    Benefits of social vs. non-social feedback on learning and generosity. Results from the Tipping Game

    Front. Psychol.

    (2014)
  • J.P. Mitchell

    Encoding-specific effects of social cognition on the neural correlates of subsequent memory

    J. Neurosci.

    (2004)
  • K.S. LaBar et al.

    Cognitive neuroscience of emotional memory

    Nat. Rev. Neurosci.

    (2006)
  • K. Chawarska

    Limited attentional bias for faces in toddlers with autism spectrum disorders

    Arch. Gen. Psychiatry

    (2010)
  • Y. Kikuchi

    Atypical disengagement from faces and its modulation by the control of eye fixation in children with autism spectrum disorder

    J. Autism Dev. Disord.

    (2011)
  • K.K. Stavropoulos et al.

    Reward sensitivity to faces versus objects in children: an ERP study

    Soc. Cogn. Affect. Neurosci.

    (2014)
  • B.C. Reeb-Sutherland

    One-month-old human infants learn about the social world while they sleep

    Dev. Sci.

    (2011)
  • T. Grossmann et al.

    The development of the social brain in human infancy

    Eur. J. Neurosci.

    (2007)
  • T. Farroni

    Eye contact detection in humans from birth

    Proc. Natl. Acad. Sci. U.S.A.

    (2002)
  • T. Farroni

    Mechanisms of eye gaze perception during infancy

    J. Cogn. Neurosci.

    (2004)
  • M. Gluckman et al.

    Attentional capture by social stimuli in young infants

    Front. Psychol.

    (2013)
  • J.S. Noland

    Better working memory for non-social targets in infant siblings of children with Autism Spectrum Disorder

    Dev. Sci.

    (2010)
  • W. Sanefuji

    Development of preference for conspecific faces in human infants

    Dev. Psychol.

    (2014)
  • F. Farzin

    Piecing it together: infants’ neural responses to face and object structure

    J. Vis.

    (2012)
  • T. Grossmann

    Early cortical specialization for face–to–face communication in human infants

    Proc. Biol. Sci.

    (2008)
  • C.H. Roder

    Impairment of gaze-directed spatial coding in recent-onset schizophrenia

    Q. J. Exp. Psychol. (Hove)

    (2015)
  • M. Dalmaso

    Is social attention impaired in schizophrenia? Gaze, but not pointing gestures, is associated with spatial attention deficits

    Neuropsychology

    (2013)
  • P.O. Harvey et al.

    Neural correlates of recognition memory of social information in people with schizophrenia

    J. Psychiatry Neurosci.

    (2013)
  • A.E. Pinkham

    An intact threat superiority effect for nonsocial but not social stimuli in schizophrenia

    J. Abnorm. Psychol.

    (2014)
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