Role of N-methyl-D-aspartate receptors in action-based predictive coding deficits in schizophrenia

Published in final edited form as:Biol Psychiatry. 2017 March 15; 81(6): 514–524. doi:10.1016/j.biopsych.2016.06.019.BACKGROUND: Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia. METHODS: In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared. RESULTS: N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen’s d = 1.14) and schizophrenia (Cohen’s d = .85). CONCLUSIONS: Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.This work was supported by AstraZeneca for an investigator-initiated study (DHM) and the National Institute of Mental Health Grant Nos. R01 MH-58262 (to JMF) and T32 MH089920 (to NSK). JHK was supported by the Yale Center for Clinical Investigation Grant No. UL1RR024139 and the US National Institute on Alcohol Abuse and Alcoholism Grant No. P50AA012879. (AstraZeneca for an investigator-initiated study (DHM); R01 MH-58262 - National Institute of Mental Health; T32 MH089920 - National Institute of Mental Health; UL1RR024139 - Yale Center for Clinical Investigation; P50AA012879 - US National Institute on Alcohol Abuse and Alcoholism)Accepted manuscrip

LPS-Induced Upregulation of SHIP Is Essential for Endotoxin Tolerance

AbstractAn initial exposure to lipopolysaccharide (LPS) induces a transient state of hyporesponsiveness to a subsequent challenge with LPS. The mechanism underlying this phenomenon, termed endotoxin tolerance, remains poorly understood despite a recent resurgence of interest in this area. We demonstrate herein that SHIP−/− bone marrow-derived macrophages (BMmφs) and mast cells (BMMCs) do not display endotoxin tolerance. Moreover, an initial LPS treatment of wild-type BMmφs or BMMCs increases the level of SHIP, but not SHIP2 or PTEN, and this increase is critical for the hyporesponsiveness to subsequent LPS stimulation. Interestingly, this increase in SHIP protein is mediated by the LPS-induced production of autocrine-acting TGFβ and neutralizing antibodies to TGFβ block LPS-induced endotoxin tolerance. In vivo studies with SHIP+/+ and SHIP−/− mice confirm these in vitro findings and show a correlation between the duration of endotoxin tolerance and elevated SHIP levels

Neural computations of threat in the aftermath of combat trauma

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. By combining computational, morphological, and functional analyses, this study relates latent markers of associative threat learning to overt post-traumatic stress disorder (PTSD) symptoms in combat veterans. Using reversal learning, we found that symptomatic veterans showed greater physiological adjustment to cues that did not predict what they had expected, indicating greater sensitivity to prediction errors for negative outcomes. This exaggerated weighting of prediction errors shapes the dynamic learning rate (associability) and value of threat predictive cues. The degree to which the striatum tracked the associability partially mediated the positive correlation between prediction-error weights and PTSD symptoms, suggesting that both increased prediction-error weights and decreased striatal tracking of associability independently contribute to PTSD symptoms. Furthermore, decreased neural tracking of value in the amygdala, in addition to smaller amygdala volume, independently corresponded to higher PTSD symptom severity. These results provide evidence for distinct neurocomputational contributions to PTSD symptoms

The Purdue Extension and Indiana CTSI's Community Health Partnerships collaboration: An innovative, generalizable, state-wide model to help communities build a culture of health

The Indiana Clinical and Translational Sciences Institute's Community Engagement Partners-Purdue Extension collaborative model demonstrates tremendous potential for creating state-wide programmatic efforts and improvements in both the health culture and status of Indiana residents across the state. It can serve as a prototype not only for others interested in pursuing wide geographic health improvements through Clinical and Translational Sciences Award-Cooperative Extension partnerships but also for broader collaborations among United States Department of Agriculture, National Institutes of Health, Centers for Disease Control and Prevention, state and local health departments, and health foundation efforts to improve population health

Genome-wide association study identifies glutamate ionotropic receptor GRIA4 as a risk gene for comorbid nicotine dependence and major depression

Smoking and major depression frequently co-occur, at least in part due to shared genetic risk. However, the nature of the shared genetic basis is poorly understood. To detect genetic risk variants for comorbid nicotine dependence (ND) and major depression (MD), we conducted genome-wide association study (GWAS) in two samples of African-American participants (Yale-Penn 1 and 2) using linear mixed model, followed by meta-analysis. 3724 nicotine-exposed subjects were analyzed: 2596 from Yale-Penn-1 and 1128 from Yale-Penn-2. Continuous measures (Fagerström Test for Nicotine Dependence (FTND) scores and DSM-IV MD criteria) rather than disorder status were used to maximize the power of the GWAS. Genotypes were ascertained using the Illumina HumanOmni1-Quad array (Yale-Penn-1 sample) or the Illumina HumanCore Exome array (Yale-Penn-2 sample), followed by imputation based on the 1000 Genomes reference panel. An intronic variant at the GRIA4 locus, rs68081839, was significantly associated with ND-MD comorbidity (β = 0.69 [95% CI, 0.43-0.89], P = 1.53 × 10-8). GRIA4 encodes an AMPA-sensitive glutamate receptor that mediates fast excitatory synaptic transmission and neuroplasticity. Conditional analyses revealed that the association was explained jointly by both traits. Enrichment analysis showed that the top risk genes and genes co-expressed with GRIA4 are enriched in cell adhesion, calcium ion binding, and synapses. They also have enriched expression in the brain and they have been implicated in the risk for other neuropsychiatric disorders. Further research is needed to determine the replicability of these findings and to identify the biological mechanisms through which genetic risk for each condition is conveyed

Contribution of Cystine-Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine–glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine–glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by N-acetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystine–glutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine–glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine–glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine–glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP

Early-Childhood Temperament Moderates the Prospective Associations of Coping with Adolescent Internalizing and Externalizing Symptoms

While appraisal and coping are known to impact adolescent psychopathology, more vulnerable or resilient responses to stress may depend on individual temperament. This study examined early life temperament as a moderator of the prospective relations of pre-adolescent appraisal and coping with adolescent psychopathology. The sample included 226 (62% female, 14–15 years) adolescents with assessments starting at 3 years of age. Adolescents were predominately White (12% Black 9% Asian, 11% Latinx, 4% Multiracial, and 65% White). Observed early-childhood temperament (fear, frustration, executive control, and delay ability) were tested as moderators of pre-adolescent coping (active and avoidant) and appraisal (threat, positive) on internalizing and externalizing symptoms during the pandemic. Interaction effects were tested using regression in R. Sex and family context of stress were covariates. Early-childhood temperament was correlated with pre-adolescent symptoms, however, pre-adolescent appraisal and coping but not temperament predicted adolescent psychopathology. Frustration moderated the relations of active and avoidant coping and positive appraisal to symptoms such that coping and appraisal related to lower symptoms only for those low in frustration. Executive control moderated the associations of avoidant coping with symptoms such that avoidance reduced the likelihood of symptoms for youth low in executive control. Findings underscore the role of emotionality and self-regulation in youth adjustment, with the impact of coping differing with temperament. These findings suggest that equipping youth with a flexible assortment of coping skills may serve to reduce negative mental health outcomes

Genome-wide significant loci for addiction and anxiety

Background Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. Methods Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. Results Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD = 3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD = 2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg = 0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD = 3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD = 3.425). Conclusions This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics