Trends in Neurosciences
OpinionSocial Preference and Glutamatergic Dysfunction: Underappreciated Prerequisites for Social Dysfunction in Schizophrenia
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.
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Cited by (24)
Aberrant Effective Connectivity During Eye Gaze Processing Is Linked to Social Functioning and Symptoms in Schizophrenia
2023, Biological Psychiatry: Cognitive Neuroscience and NeuroimagingNeuroprotective effect of the standardised extract of Bacopa monnieri (BacoMind) in valproic acid model of autism spectrum disorder in rats
2022, Journal of EthnopharmacologyCitation Excerpt :These results are in concordance with the study by Sandhya et al., (2012), where administration of BM in the autistic pups at adolescence (PND 30–40) as well as adulthood (PND 90–110) resulted in significant improvement in the social behaviors in the ASD pups (Sandhya et al., 2012). The social behavior deficits in the VPA exposed rats could be assigned to the over expression of the glutamatergic receptor activity in the brain (Lee and Green, 2016). The animals from the valproic acid exposed group displayed lower sociability and social novelty.
Dynamic causal modeling of eye gaze processing in schizophrenia
2021, Schizophrenia ResearchCitation Excerpt :Our finding suggests that disrupted E/I balances are pervasive throughout the visual processing stream in schizophrenia, characterized by increased inhibition in low-level visual cortex and disinhibition in regions higher up in the hierarchy. Such deviations may originate from glutamatergic (Krystal et al., 2017) and GABAergic dysfunctions (Taylor and Tso, 2015; Tso et al., 2015), which both have been hypothesized to contribute to social cognitive impairment and social disability in schizophrenia (Lee and Green, 2016). In addition to abnormal self-connections, SZ also exhibited altered strengths in inter-regional connections during gaze processing.
Effects of post-weaning social isolation on social behaviors and oxytocinergic activity in male and female rats
2019, HeliyonCitation Excerpt :Nevertheless, there were no demonstrable effects of isolation on male social preference and approach behaviors in the current study. However, in the social preference test, even male control rats did not display greater preference for the social stimulus over the non-social stimulus, which has been shown previously in normal rodents [37, 38] and healthy humans [23]. Although there is no clear explanation for the disagreement of our results with previous findings, differences in experimental conditions, such as the species and strain of subjects, testing apparatus, and social stimuli, might be responsible.
Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944
2017, Experimental NeurologyCitation Excerpt :There is evidence to suggest that Cav3.2 T-type channels contribute to the regulation of N-methyl-d-aspartate receptor (NMDAR) transmission as enhanced glutamatergic transmission occurs with expression of the childhood absence epilepsy-linked mutant Cav3.2 channel, hCav3.2 (C456S) (Wang et al., 2015). NMDAR dysfunction may underlie sociability deficits observed in psychiatric disorders such as schizophrenia (Lee and Green, 2016). For example, genetically modified mice with NMDAR hypofunction and wild mice treated with the NMDAR antagonist, MK801, showed decreased preference for the stranger mouse in the sociability task (Halene et al., 2009; Moy et al., 2013).
Therapeutic potential of agmatine for CNS disorders
2017, Neurochemistry InternationalCitation Excerpt :Another study showed that although agmatine per se did not alter PPI response, pretreatment with this compound attenuated the disruptive effect of phencyclidine (PCP) (a noncompetitive NMDA receptor antagonist) on PPI in mice (Palsson et al., 2008). Indeed, NMDA receptor dysfunction has been indicated as one of the predominant mechanisms underlying the pathophysiology of schizophrenia (Coyle, 2012; Goff and Coyle, 2001; Lee and Green, 2016). In line with this, PCP reduced agmatine levels in CA1 hippocampal region (Knox et al., 2014).