Recently identified candidate susceptibility genes for schizophrenia are likely to play, important roles in the pathophysiology of the illness. It is also clear, however, that the etiologic, contribution of these genes is not only via their own functions but also through interactions with other, genes and environmental factors. Genetic, transgenic and postmortem brain studies support a, potential role for NRG1-erbB4 signaling in schizophrenia. Embedded in the results of these studies, however, are clues to the notion that NRG1-erbB4 signaling does not act alone but in conjunction with, other pathways. This article aims to re-evaluate the evidence for the role of neuregulin 1 (NRG1)-erbB4 signaling in schizophrenia by focusing on its interactions with other candidate susceptibility, pathways. In addition, we consider molecular substrates upon which the NRG1-erbB4 and other, candidate pathways converge contributing to susceptibility for the illness (schizophrenia interactome). Glutamatergic signaling can be an interesting candidate for schizophrenia interactome. Schizophrenia is associated with NMDA receptor hypofunction and moreover, several susceptibility genes for, schizophrenia converge on NMDA receptor signaling. These candidate genes influence NMDA receptor, signaling via diverse mechanisms, yet all eventually impact on protein composition of NMDA receptor, complexes. Likewise, the protein associations in the receptor complexes can themselves modulate, signaling molecules of candidate genes and their pathways. Therefore, protein-protein interactions in the NMDA receptor complexes can mediate reciprocal interactions between NMDA receptor function, and susceptibility candidate pathways including NRG1-erbB4 signaling and thus can be a, schizophrenia interactome.
"Therefore, it is important to investigate the role of clinical and genetic factors in the therapeutic outcome in patients with differential range of disease severity (Chen et al. 2009). A number of genome-wide association studies (GWASs), postmortems, and animal studies (Ikeda et al. 2010; McClay et al. 2011) have implicated the role of susceptibility genes and related neurodevelopment pathways in schizophrenia pathophysiology and treatment outcome (Banerjee et al. 2010; Iasevoli et al. 2014). Since antipsychotics are neurogenic in action, research has focused on the involvement of neurodevelopmental genes in antipsychotic response (Newton and Duman 2007). "
[Show abstract][Hide abstract] ABSTRACT: Neurodevelopmental and neuroimmunological genes critically regulate antipsychotic treatment outcome. We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo-European and Dravidian ancestry, segregated by disease severity. Meta-analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27–2.52), P = 7.62 × 10−4; rs4586: OR (95% CI) = 1.74 (1.24–2.43), P = 1.13 × 10−3] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36–0.78), P = 1.44 × 10−3] in low severity group; and, ADCY2 [rs1544938: OR (95% CI) = 0.36 (0.19–0.65), P = 7.68 × 10−4] and NRG1 [rs13250975, OR (95% CI) = 0.42 (0.23–0.79), P = 6.81 × 10−3; rs17716295, OR (95% CI) = 1.78 (1.15–2.75), P = 8.71 × 10−3] in high severity group, with incomplete response toward antipsychotics. To our knowledge, this is the first study to identify genetic polymorphisms associated with the efficacy of antipsychotic treatment of schizophrenia patients from two major India populations.
"This negative finding is coherent with previous data, which did not show an association between cognition and genetic variation in NRG in schizophrenia . The variety of functions subserved by NRG in the brain's development suggests the possibility that other SNP or haplotypes related to NRG1 and/or ERBB4 may be associated to cognitive deficit and/or disorganized cortical activity in schizophrenia [25,26]. "
[Show abstract][Hide abstract] ABSTRACT: Background
Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1–4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance.
We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype.
Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia.
Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia.
Annals of General Psychiatry 06/2014; 13(18). DOI:10.1186/1744-859X-13-18 · 1.40 Impact Factor
"Evidence from linkage studies, post-mortem schizophrenic brains and transgenic animal models has suggested that perturbations in the NRG1–ErbB4 signaling pathway may contribute to the pathophysiology of schizophrenia (Harrison and Law, 2006; Mei and Xiong, 2008). Recent studies have pointed to the possibility that this pathway may collaborate with other molecules (Banerjee et al., 2010), of which the N-methyl-D-aspartate receptor (NMDAR) pathway is of particular interest considering the leading role of the NMDAR hypofunction in schizophrenia (Coyle et al., 2003; Moghaddam, 2003). The potential cross-talk between these two pathways has a structural basis given that ErbB4 binds and colocalizes with the postsynaptic scaffold protein PSD-95 (Garcia et al., 2000; Huang et al., 2000), which further interacts with NMDAR (Kornau et al., 1995). "
[Show abstract][Hide abstract] ABSTRACT: The neuregulin 1 (NRG1)-ErbB4 signaling pathway has been implicated in the pathophysiology of schizophrenia. Recent studies suggest that this pathway may interact with the N-methyl-D-aspartate receptor (NMDAR) via the postsynaptic scaffold protein PSD-95. This interaction is of particular interest given the leading role of the NMDAR hypofunction in schizophrenia. The present study investigated the short- and long-term effects of chronic NMDAR blockade on the functional interaction between the two systems in rat prefrontal cortex and hippocampus using immunoprecipitation. Adult male Wistar rats were treated intraperitoneally with MK-801 (0.25mg/kg) or saline for 28days. Twenty-four hours after the last injection, the associations of ErbB4 with PSD-95 and NMDAR were enhanced in the prefrontal cortex, whereas only phosphorylated-ErbB4 relative to ErbB4 was increased in the hippocampus. These effects, however, were not detectable 12days after the last MK-801 treatment, indicating the reversible nature of these changes. We also investigated the effects of chronic MK-801 treatment on locomotion, prepulse inhibition, recognition memory, and spatial working memory. The results showed that this treatment led to decreased locomotor activity, reduced exploration in the center arena, and elevated startle magnitudes, indicating an anxiety-like phenotype. Taken together, our findings suggest that the NRG1-ErbB4 signaling could be modulated by repeated NMDAR blockade, and provide further evidence for the cross-talk between the two signaling pathways.
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