Interactions In Schizophrenia Research Articles

Faulty Executive Attention and Memory Interactions in Schizophrenia: Prefrontal Gray Matter Volume and Neuropsychological Impairment.

We hypothesized that neuropsychological disturbance in schizophrenia (SZ) may reflect faulty interactions of executive attention and episodic memory, emanating, in part, from reduced prefrontal cortex (PFC) gray matter volume. Participants with SZ (n = 84) and age-matched (n = 77) controls completed both the Wisconsin Card Sorting Test (WCST) and the Wechsler Memory Scale-Third Edition (WMS-III), used, respectively, as measures of executive attention and episodic memory. A subset of SZ (n = 27) and control (n = 17) groups also had available 3-T magnetic resonance imaging (MRI) studies of the PFC. For SZ, but not control groups, neuropsychological results indicated that executive attention interacted significantly with episodic memory, with failures of executive attention, as reflected by increased WCST perseverative errors, directly linked to poor performance on the WMS-III measure of delayed visual recall of action scenes. MRI results indicated reduced left PFC gray matter volume for SZ group, which in turn correlated significantly with their deficits in visual memory but not in executive attention. Results showed that 61% of the variance in neuropsychological performance in the SZ group was attributed to gray matter volume of left inferior prefrontal gyrus gray matter volume. PFC-mediated failure of executive attention-episodic memory interactions may represent an important mechanism in neuropsychological disturbance in SZ.

Choroid Plexus Enlargement and Allostatic Load in Schizophrenia.

Although schizophrenia is a brain disorder, increasing evidence suggests that there may be body-wide involvement in this illness. However, direct evidence of brain structures involved in the presumed peripheral-central interaction in schizophrenia is still unclear. Seventy-nine previously treatment-naïve first-episode schizophrenia patients who were within 2-week antipsychotics initial stabilization, and 41 age- and sex-matched healthy controls were enrolled in the study. Group differences in subcortical brain regional structures measured by MRI and the subclinical cardiovascular, metabolic, immune, and neuroendocrine biomarkers as indexed by allostatic load, and their associations were explored. Compared with controls, patients with schizophrenia had significantly higher allostatic load (P = .001). Lateral ventricle (P < .001), choroid plexus (P < .001), and thalamus volumes (P < .001) were significantly larger, whereas amygdala volume (P = .001) was significantly smaller in patients. The choroid plexus alone was significantly correlated with higher allostatic load after age, sex, education level, and the total intracranial volume were taken into account (t = 3.60, P < .001). Allostatic load was also significantly correlated with PANSS positive (r = 0.28, P = .016) and negative (r = -0.31, P = .008) symptoms, but in opposite directions. The peripheral multisystemic and central nervous system abnormalities in schizophrenia may interact through the choroid plexus during the early stage of the illness. The choroid plexus might provide a sensitive structural biomarker to study the treatment and prevention of brain-periphery interaction abnormalities in schizophrenia.

Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study.

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene-environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS-SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early-life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS-SCZ at 75% with alternative cut-points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures.

The SNAP25 Interactome in Ventromedial Caudate in Schizophrenia Includes the Mitochondrial Protein ARF1

Abnormalities of SNAP25 (synaptosome-associated protein 25) amount and protein–protein interactions occur in schizophrenia, and may contribute to abnormalities of neurotransmitter release in patients. However, presynaptic terminal function depends on multiple subcellular mechanisms, including energy provided by mitochondria. To explore the SNAP25 interactome in schizophrenia, we immunoprecipitated SNAP25 along with interacting proteins from the ventromedial caudate of 15 cases of schizophrenia and 13 controls. Proteins were identified with mass spectrometry-based proteomics. As well as 15 SNARE- (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) associated proteins, we identified 17 mitochondria-associated and four other proteins. The mitochondrial small GTPase ARF1 (ADP-ribosylation factor 1) was identified in eight schizophrenia SNAP25 immunoprecipitates and none from controls (P = 0.004). Although the ARF1–SNAP25 interaction may be increased, immunoblotting demonstrated 21% lower ARF1-21 (21 kiloDaltons) in schizophrenia samples (P = 0.04). In contrast, the mitochondrial protein UQCRC1 (ubiquinol-cytochrome c reductase core protein 1) did not differ. Lower ARF1-21 levels were associated with the previously reported increased SNAP25–syntaxin interaction in schizophrenia (r = −0.39, P = 0.04). Additional immunoprecipitation studies confirmed the ARF1-21–SNAP25 interaction, independent of UQCRC1. Both ARF1 and SNAP25 were localized to synaptosomes. Confocal microscopy demonstrated co-localization of ARF1 and SNAP25, and further suggested fivefold enrichment of ARF1 in synaptosomes containing an excitatory marker (vesicular glutamate transporter) compared with synaptosomes containing an inhibitory marker (vesicular GABA transporter). The present findings suggest an association between abnormalities of SNARE proteins involved with vesicular neurotransmission and the mitochondrial protein ARF1 that may contribute to the pathophysiology of schizophrenia.

Cooperation and sensitivity to social feedback during group interactions in schizophrenia

Patients with schizophrenia show reduced cooperation and less sensitivity to social cues in pairwise interactions, however, it remains unclear whether these mechanisms are also present in interactions within social groups. We used a public goods game to investigate cooperation and sensitivity to social feedback in group interactions in 27 patients with schizophrenia and 27 healthy controls. Participants played 40 trials in two conditions: 1) no fine (20 trials): participants had the choice of investing into the public good (i.e. cooperating) or not (i.e. defecting), 2) fine (20 trials): participants had the same choice but defectors could be punished by the other players. On the first trial, patients invested less in the public good than healthy controls. In the no fine condition, controls decreased their investments over time, but patients did not. The possibility of being fined for defecting and actually being fined led to significantly higher cooperation in both groups. This shows that the groups were equally sensitive to social enforcement and social feedback. Our findings suggest that patients tend to approach social group interactions with less cooperative behaviour, which could contribute to social dysfunction in daily-life. However, an intact sensitivity to social enforcement and feedback indicates that patients can adjust their behaviour accordingly in group interactions.

10. THE MOLECULAR MECHANISMS OF SCHIZOPHRENIA FROM GLIAL CELLS PERSPECTIVE

Overall : In the past decade, rapid advances in the field of neuroscience resulted in a dramatic paradigm shift in the way we understand the role of glia in normal brain functions and brain disorder pathology. A growing body of evidence shows that diversified populations of astrocytes, microglia, oligodendrocyte precursors and mature oligodendrocytes play a critical role in the regulation of synaptic functions, blood-brain barrier, immune response regulation, myelination and axonal conduction, and in the synthesis of the extracellular matrix, a key regulator of neural plasticity. Building on this evidence, exciting new findings are beginning to emerge, shedding light on glia abnormalities in schizophrenia and their impact these functions. This symposium aims to discuss and integrate the current state of knowledge on direct evidence for glial abnormalities in schizophrenia and their underlying mechanisms.Dr. Juliana Nascimiento will present novel findings on the effects of NMDAr antagonists and antipsychotics influence glial cell lines and 3D cultures as neurospheres and cerebral organoids. Results from these studies point to the central role of glycolysis, EIF2 signaling and translational machinery in oligodendrocytes and astrocytes. Dr. Paul Klauser will report on elegant investigations on the implication of developmental redox imbalance inducing oxidative stress leading to impairments of oligodendrocytes, myelin formation and eventually to the disruption of white fibers integrity and conductivity, especially in brain regions where the metabolic demand is high. In patients, alterations of white matter were found to be inversely correlated with blood levels of GSH precursor cysteine and could be prevented by the early administration of the antioxidant N-acetyl cysteine. Dr. Sabina Berretta will discuss recent findings on novel modalities of interaction between glial cells, extracellular matrix and neurons, postulated to affect synaptic structural plasticity and axonal conductance. A growing body of evidence from her group shows disruption of such interactions in schizophrenia, potentially contributing to synaptic pathology and impacting neural connectivity. Dr. Dost Ongur will build on previous work showing abnormal diffusion of neuron-specific metabolite NAA in frontal white matter in patients with chronic schizophrenia in the absence of abnormalities in the diffusion of non-specific metabolites Cr and Cho. State-of-the-art recent studies on first episode psychosis patients and matched healthy controls show that NAA diffusion is normal in first episode patients but Cr and Cho diffusion is abnormal, suggesting that white matter abnormalities in non-neuronal elements in early phases of schizophrenia which are followed by neuronal damage in chronic disease.

Brain correlates of recognition of communicative interactions from biological motion in schizophrenia.

Recognition of communicative interactions is a complex social cognitive ability which is associated with a specific neural activity in healthy individuals. However, neural correlates of communicative interaction processing from whole-body motion have not been known in patients with schizophrenia (SCZ). Therefore, the current study aims to examine the neural activity associated with recognition of communicative interactions in SCZ by using displays of the dyadic interactions downgraded to minimalistic point-light presentations. Twenty-six healthy controls (HC) and 25 SCZ were asked to judge whether two agents presented only by point-light displays were communicating or acting independently. Task-related activity and functional connectivity of brain structures were examined with General Linear Model and Generalized Psychophysiological Interaction approach, respectively. HC were significantly more efficient in recognizing each type of action than SCZ. At the neural level, the activity of the right posterior superior temporal sulcus (pSTS) was observed to be higher in HC compared with SCZ for communicative v. individual action processing. Importantly, increased connectivity of the right pSTS with structures associated with mentalizing (left pSTS) and mirroring networks (left frontal areas) was observed in HC, but not in SCZ, during the presentation of social interactions. Under-recruitment of the right pSTS, a structure known to have a pivotal role in social processing, may also be of importance for higher-order social cognitive deficits in SCZ. Furthermore, decreased task-related connectivity of the right pSTS may result in reduced use of additional sources of information (for instance motor resonance signals) during social cognitive processing in schizophrenia.

Understanding epigenetics of schizophrenia in the backdrop of its antipsychotic drug therapy

The diatheses of gene and environment interaction in schizophrenia (SCZ) are becoming increasingly evident. Genetic and epigenetic backgrounds are being considered in stratifying and addressing phenotypic variation and drug response in SCZ. But how much of these epigenetic alterations are the primary contributing factor, toward disease pathogenesis and drug response, needs further clarity. Evidence indicates that antipsychotic drugs can also alter the epigenetic homeostasis thereby inducing pharmacoepigenomic effects. We re-examine the context of epigenetics in disease pathogenesis and antipsychotic drug therapy in SCZ to understand how much of these observations act as real indicators of the disease or therapeutic response. We propose that epigenetic viewpoint in SCZ needs to be critically examined under the genetic, epigenetic and pharmacoepigenetic background.

SA22. Impaired Processing of Social Context During Interpersonal Interactions in Schizophrenia

Background: Schizophrenia is an illness with devastating social consequences. Reduced interpersonal trust and the inability to pick up social contextual information have been suggested as important determinants underlying reduced social functioning in schizophrenia. During social encounters, healthy individuals derive a mental model of their interaction partner via feedback from actual behavior (bottom-up processing) and social contextual information about the other (top-down processing). To date, few studies investigated the impact of social context sensitivity on trust and social decision-making in real-time social interactions in schizophrenia. Methods: We examined social context sensitivity and its effects on interpersonal trust during social decision-making in an interactive 20-round trust game in 36 patients with a diagnosis in the schizophrenia spectrum and 46 healthy controls. The task was manipulated to measure the impact of top-down processing on social decision-making by presenting no, positive, or negative contextual information about the counterpart’s trustworthiness prior to each game round. In fact, all 3 counterparts were playing according to the same preprogrammed algorithm, where trusting behavior was rewarded with higher repayments. We used multilevel regression analyses to account for multiple observations within subjects. We examined differences in baseline trust (i.e., first investment), learning to adapt trusting behavior over time and changes in trust in response to context between groups, taking into account age, gender, and general intelligence. Results: At baseline, where top-down processing is not yet influenced by bottom-up learning mechanisms, there was a significant Group × Context interaction. In patients, there was no significant context effect on their initial investments, but controls invested more in the positive and less in the negative context condition compared to the no context condition. For overall investments, there were significant Group × Trial number interactions in the no context and the negative condition, revealing that patients did not show a learning effect of the provided behavioral feedback, whereas controls did. Conclusion: This study shows that patients with schizophrenia are less sensitive to social contextual information than controls. The inability to adapt trusting behavior after contextual information suggests that patients have a general insensitivity to social contextual information. Patients also seem to have problems in bottom-up processing of direct behavioral feedback, as they do not change their trust accordingly. A combination of top-down and bottom-up processing impairments in schizophrenia may result in impaired trust and social functional deficits.

SU21. Reduced Inclination to Cooperate During Group Interactions in Schizophrenia

SU21. Reduced Inclination to Cooperate During Group Interactions in Schizophrenia

SU120. Urban Upbringing Influences Response to Social Feedback

Background: Growing up in an urban environment is associated with a higher incidence of schizophrenia. The effects of urbanicity seem particularly pronounced during development. It has been hypothesized that urbanicity could be a proxy for social stress, which might account for disturbed social interactions and trust in the disorder. Yet, how urbanicity affects trust and the dynamics of social interactions in schizophrenia has not been investigated experimentally. Previous studies have suggested that a key feature of disturbed trust in schizophrenia is a lack of sensitivity to the behavior of others. We hypothesized that higher exposure to urban environment during development is associated with a greater insensitivity to social signals. Results: Patients showed lower basic trust than controls, but mean investments in both the cooperative and unfair condition did not differ between groups. Patients grew up in marginally more urban environments (P = .07). Urbanicity was not associated with basic trust. In the cooperative condition, there was a significant interaction between group, trial number, and urbanicity (P = .002). Controls adjusted their levels of trust during interactions with positive and negative feedback, regardless of urbanicity. Patients however adjusted their investments less with increasing urbanicity: in the highest urbanicity group, patients made no behavioral adjustments over trials, but the other urbanicity levels were associated with significant increases in trust. In the unfair condition, the interaction reached trend level (P = .086); however, a similar pattern of effects emerged whereby higher urbanicity correlated with less decline in trust, thus with less adaptive behavior. Conclusion: High levels of urbanicity in psychosis patients but not in controls are associated with increasing insensitivity to the behavior of others, particularly during cooperation. This insensitivity to others could aggravate social dysfunction and might be driven by prolonged social stress exposure and a desensitized emotional and reward systems in the brain. Future (neuroimaging) studies will be necessary to investigate the mechanisms underlying the influence of urbanicity on trust in order to corroborate our findings. Methods: We used 2 multiround trust games to measure the trust during repeated social interactions and basic trust toward unknown others. Twenty-four adolescents with nonaffective psychosis and 24 age-matched healthy controls (mean age 19.6, SD = 1.6) played the 20-round trust games with a preprogrammed cooperative (returning more) and unfair partner (returning less than invested), to probe under which circumstances urbanicity affects reactions to social behavior. Urbanicity was defined as the density of addresses per km2, with 5 levels from rural to very urban. Mean urbanicity exposure over 0–15 years of age was used. All analyses (multilevel regressions) were controlled for IQ and gender.

A neuroimaging study of emotion-cognition interaction in schizophrenia: the effect of ziprasidone treatment.

Functional and structural brain changes associated with the cognitive processing of emotional visual stimuli were assessed in schizophrenic patients after 16weeks of antipsychotic treatment with ziprasidone. Forty-five adults aged 18 to 40 were recruited: 15 schizophrenia patients (DSM-IV criteria) treated with ziprasidone (mean daily dose=120mg), 15 patients treated with other antipsychotics, and 15 healthy controls who did not receive any medication. Functional and structural neuroimaging data were acquired at baseline and 16weeks after treatment initiation. In each session, participants selected stimuli, taken from standardized sets, based on their emotional valence. After ziprasidone treatment, several prefrontal regions, typically involved in cognitive control (anterior cingulate and ventrolateral prefrontal cortices), were significantly activated in patients in response to positive versus negative stimuli. This effect was greater whenever they had to select negative compared to positive stimuli, indicating an asymmetric effect of cognitive treatment of emotionally laden information. No such changes were observed for patients under other antipsychotics. In addition, there was an increase in the brain volume commonly recruited by healthy controls and patients under ziprasidone, in response to cognitive processing of emotional information. The structural analysis showed no significant changes in the density of gray and white matter in ziprasidone-treated patients compared to patients receiving other antipsychotic treatments. Our results suggest that functional changes in brain activity after ziprasidone medication precede structural and clinical manifestations, as markers that the treatment is efficient in restoring the functionality of prefrontal circuits involved in processing emotionally laden information in schizophrenia.

Aberrant intra-salience network dynamic functional connectivity impairs large-scale network interactions in schizophrenia

Aberrant functional interactions between several large-scale networks, especially the central executive network (CEN), the default mode network (DMN) and the salience network (SN), have been postulated as core pathophysiologic features of schizophrenia; however, the attributing factors of which remain unclear. The study employed resting-state fMRI with 77 participants (42 patients and 35 controls). We performed dynamic functional connectivity (DFC) and functional connectivity (FC) analyses to explore the connectivity patterns of these networks. Furthermore, we performed a structural equation model (SEM) analysis to explore the possible role of the SN in modulating network interactions. The results were as follows: (1) The inter-network connectivity showed decreased connectivity strength and increased time-varying instability in schizophrenia; (2) The SN manifested schizophrenic intra-network dysfunctions in both the FC and DFC patterns; (3) The connectivity properties of the SN were effective in discriminating controls from patients; (4) In patients, the dynamic intra-SN connectivity negatively predicted the inter-network FC, and this effect was mediated by intra-SN connectivity strength. These findings suggest that schizophrenia show systematic deficits in temporal stability of large-scale network connectivity. Furthermore, aberrant network interactions in schizophrenia could be attributed to instable intra-SN connectivity and the dysfunction of the SN may be an intrinsic biomarker of the disease.

Schizophrenia among patients with systemic lupus erythematosus: population-based cross-sectional study.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease involving multiple organs, including the central nervous system. Evidence of immune dysfunction exists also in schizophrenia, a psychiatric illness involving chronic or recurrent psychosis. The aim of our study was to investigate if there is an epidemiological association between SLE and schizophrenia. A cross-sectional study was conducted comparing patients with SLE with age and gender-matched controls regarding the proportion of patients with comorbid schizophrenia. χ 2- and t-tests were used for univariate analysis, and interaction of schizophrenia with SLE across strata of covariates was checked. A logistic regression model was used for multivariate analysis. The study was performed utilising the medical database of Clalit Health Services in Israel. The study included 5018 patients with SLE and 25 090 controls. SLE patients had a female predominance, and a higher proportion of smoking compared with age and sex-matched controls. In multivariate analysis, SLE was found to be independently associated with schizophrenia while controlling for age, gender, socioeconomic status (SES) and smoking (OR 1.33, p = 0.042). We found a positive association between SLE and schizophrenia across patients of different age, gender and SES. This association can contribute to understanding the pathophysiology of the two disorders and may also have clinical implications for earlier as well as better diagnosis and treatment.

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models.

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia.

Cognitive endophenotypes, gene–environment interactions and experience-dependent plasticity in animal models of schizophrenia

Schizophrenia is a devastating brain disorder caused by a complex and heterogeneous combination of genetic and environmental factors. In order to develop effective new strategies to prevent and treat schizophrenia, valid animal models are required which accurately model the disorder, and ideally provide construct, face and predictive validity. The cognitive deficits in schizophrenia represent some of the most debilitating symptoms and are also currently the most poorly treated. Therefore it is crucial that animal models are able to capture the cognitive dysfunction that characterizes schizophrenia, as well as the negative and psychotic symptoms. The genomes of mice have, prior to the recent gene-editing revolution, proven the most easily manipulable of mammalian laboratory species, and hence most genetic targeting has been performed using mouse models. Importantly, when key environmental factors of relevance to schizophrenia are experimentally manipulated, dramatic changes in the phenotypes of these animal models are often observed. We will review recent studies in rodent models which provide insight into gene–environment interactions in schizophrenia. We will focus specifically on environmental factors which modulate levels of experience-dependent plasticity, including environmental enrichment, cognitive stimulation, physical activity and stress. The insights provided by this research will not only help refine the establishment of optimally valid animal models which facilitate development of novel therapeutics, but will also provide insight into the pathogenesis of schizophrenia, thus identifying molecular and cellular targets for future preclinical and clinical investigations.

Mother-infant interaction in schizophrenia: transmitting risk or resilience? A systematic review of the literature.

PurposeThe parent–infant relationship is an important context for identifying very early risk and resilience factors and targets for the development of preventative interventions. The aim of this study was to systematically review studies investigating the early caregiver–infant relationship and attachment in offspring of parents with schizophrenia.MethodsWe searched computerized databases for relevant articles investigating the relationship between early caregiver–infant relationship and outcomes for offspring of a caregiver with a diagnosis of schizophrenia. Studies were assessed for risk of bias.ResultsWe identified 27 studies derived from 10 cohorts, comprising 208 women diagnosed with schizophrenia, 71 with other psychoses, 203 women with depression, 59 women with mania/bipolar disorder, 40 with personality disorder, 8 with unspecified mental disorders and 119 non-psychiatric controls. There was some evidence to support disturbances in maternal behaviour amongst those with a diagnosis of schizophrenia and there was more limited evidence of disturbances in infant behaviour and mutuality of interaction.ConclusionsFurther research should investigate both sources of resilience and risk in the development of offspring of parents with a diagnosis of schizophrenia and psychosis. Given the lack of specificity observed in this review, these studies should also include maternal affective disorders including depressive and bipolar disorders.Electronic supplementary materialThe online version of this article (doi:10.1007/s00127-015-1127-x) contains supplementary material, which is available to authorized users.

Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice.

Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizophrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies, we examined the long-term effects of PHX in heterozygous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor-1α (HIF-1α) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorticoid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene-environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specificity of the gene of interest.

Gene–environment interaction of reelin and stress in cognitive behaviours in mice: Implications for schizophrenia

Cognitive deficits are a particularly debilitating symptom group in schizophrenia. We investigated the effect of a ‘two hit’ combination of two factors implicated in schizophrenia development, reelin deficiency and stress, on cognitive behaviours in mice.Male and female heterozygous reelin mice (HRM) and wild-type (WT) controls received the stress hormone, corticosterone (CORT), during early adulthood to simulate chronic stress. The Y-maze, novel object recognition task (NORT), social interaction task and prepulse inhibition (PPI) were used to assess short-term spatial memory, visual non-spatial memory, social recognition memory and sensory gating, respectively. Reelin protein expression was measured in the prefrontal cortex (PFC) and hippocampus.CORT induced spatial memory deficits in male and female HRM but not in WT controls suggesting increased vulnerability of HRM to the effects of stress on cognition. By contrast, CORT disrupted PPI only in male WT mice, but not in male HRM, suggesting a protective role of reelin deficiency against effects of stress on PPI. Male HRM performed worse in the social recognition memory task compared to wild-type controls, irrespective of CORT treatment. No differences were detected in the NORT. Reelin protein expression was increased in the PFC of female CORT-treated HRM but there were no group differences in the hippocampus. Overall, these findings extend our understanding of the role of reelin–stress interactions in schizophrenia.

Interoception Sensitivity and Autonomic Regulation During Social Interaction in Schizophrenia

Introduction The awareness of one's body constitutes a basic experience of Self which modulates the individual engagement in social interactions. Indeed, Interoception Sensitivity (IS), an index of individual ability to represent one’s own internal body states, is implicated in the autonomic regulation in interpersonal context. Schizophrenia deficits in Self-experience and awareness, which frequently entail anomalies in self-other relationship, capture the ever-growing attention of researchers. Nevertheless, IS and autonomic regulation of schizophrenic patients in social context are completely new and not yet investigated aspects of Schizophrenia. Aim To investigate whether Schizophrenia could be associated with lower IS and with a dysfunctional autonomic regulation during social interaction. Methods 24 chronic schizophrenia patients, and a matched group of healthy controls, performed a Social and a Non-social task while respiratory sinus arrhythmia (an index of autonomic regulation) was measured. In the Social task participants viewed an experimenter performing a caress-like movement at different distances from their hand. In the Non-social task a metal stick was moved at the same distances from the participants’ hand. As measure of IS, a cardiac Mental Tacking Task was performed. Results Comparing to controls, Schizophrenia patients presented lower IS, absence of relation between IS and autonomic regulation, and an anomalous autonomic regulation in social and non-social contexts. Conclusions Deficits in Self-experience, associated with Schizophrenia, could be extended to patients’ sensitivity to internal bodily signals. Moreover, the observed altered autonomic regulation will be part of interpersonal interaction deficit frequently associated to Schizophrenia.