Neuregulin-1 and schizophrenia in the genome-wide association study era

Mostaid, Shaki; Lloyd, David B.; Liberg, Benny; Sundram, Suresh; Pereira, Avril; Pantelis, Christos; Karl, Tim; Weickert, Cynthia Shannon; Everall, Ian; Bousman, Chad

doi:10.1016/j.neubiorev.2016.06.001

Cited by 73 publications

(57 citation statements)

References 194 publications

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“…However, we observed different cytokine profiles following TLR and ErbB stimulation, which is against the possibility that our findings reflect baseline characteristics and that these immunological changes would be apparent without stimulation. Second, we did not investigate neuregulin 1-beta, which is a predominant form in the brain 16 . Third, it has not been explored how antipsychotics may modulate TLR/ErbB expression and activation.…”

Section: Discussionmentioning

confidence: 99%

“…A notable example is the profoundly characterized molecule neuregulin 1 (NRG1) and its ErbB receptors (ErbB4 and ErbB2/ErbB3 complex) 16–21 . A timely and detailed review and a meta-analysis by Mostaid et al .…”

Section: Introductionmentioning

confidence: 99%

“…A timely and detailed review and a meta-analysis by Mostaid et al . 16,22 demonstrated that, despite the fact that whole-genome association studies did not confirm a link between NRG1/ErbB genes and schizophrenia, there is substantial evidence from other types of preclinical and clinical studies that NRG1 may be relevant in the pathophysiology of schizophrenia by regulating not only synapse formation but the balance between excitatory (glutamatergic) and inhibitory (GABA-ergic) neurotransmission.…”

Section: Introductionmentioning

confidence: 99%

“…The first element of the TLR signaling pathway is the cytoplasmic Toll/Interleukin-1 (IL-1) receptor (TIR) domain, which is linked to an adaptor, MyD88 37–40 . An analysis of the statistical epistatic network of NRG1 in clinical studies of schizophrenia indicated its relationship with IL-1β 16 , which may be an important link to TLR signaling.…”

Section: Introductionmentioning

confidence: 99%

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Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Kéri

Szabó

Kelemen

2017

Sci Rep

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Current pathophysiological models of schizophrenia focus on neurodevelopmental and immunological mechanisms. We investigated a molecular pathway traditionally linked to the neurodevelopmental hypothesis (neuregulin 1 - ErbB), and pathogen-associated pattern recognition receptors associated with the immune hypothesis (Toll-like receptors, TLRs). We recruited 42 first-episode, drug-naïve patients with schizophrenia and 42 matched healthy control subjects. In monocytes TLR4/TLR5 and ErbB expressions were measured with flow-cytometry. Pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the anti-inflammatory cytokine IL-10 were determined following the stimulation of TLR4/TLR5 and ErbB. Results revealed increased TLR4/TLR5 and decreased ErbB4 expression in schizophrenia relative to the control subjects. The expression of ErbB2 and ErbB3 receptors was unaltered in schizophrenia. TLR4 stimulation resulted in lower pro-inflammatory cytokine production in schizophrenia compared to the control levels, whereas the stimulation of ErbB by neuregulin 1 led to higher pro-inflammatory cytokine levels in patients with schizophrenia relative to the control group. In healthy controls, ErbB activation was associated with a marked production of IL-10, which was dampened in schizophrenia. These results indicate that the stimulation of TLR4 and ErbB induces opposite pro-inflammatory cytokine responses in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Kéri

Szabó

Kelemen

2017

Sci Rep

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“…Similarly, Neuroregulin1 (NRG1) exhibited increased variation and emerged in the gene enrichment analysis as a gene involved in multiple cellular functions. NRG1 promotes myelination in the central nervous system (CNS) and evidence suggests an association between NRG1 and cognitive deficits linked to psychiatric disorders 89,[89][90][91][92][93][94][95] .…”

Section: Discussionmentioning

confidence: 99%

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

Roberson‐Nay

Wolen

Lapato

et al. 2018

Preprint

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Major depression (MD) is a debilitating mental health condition with peak prevalence occurring early in life. Genome-wide examination of DNA methylation (DNAm) offers an attractive complement to studies of allelic risk given it can reflect the combined influence of genes and environment.The current study used a co-twin control design to identify differentially and variably methylated regions of the genome that distinguish monozygotic (MZ) twins with and without a lifetime history of early-onset MD. The sample included 150 Caucasian monozygotic twins (73% female;Mage=17.52 SD=1.28) assessed during a developmental stage characterized by relatively distinct neurophysiological changes. All twins were generally healthy and currently free of medications with psychotropic effects. DNAm was measured in peripheral blood cells using the Infinium Human BeadChip 450K Array. MD associations were detected at 760 differentially and variably methylated probes/regions that mapped to 428 genes. Gene enrichment analyses implicated genes related to neuron structures and neurodevelopmental processes including cell-cell adhesion genes (e.g., CDHs, PCDHAs, PCDHA1C/2C). Genes previously implicated in mood and psychiatric disorders as well as chronic stress (e.g., HDAC4, NRG1) also were identified. Results indicated an association between early-onset MD and many genes and genomic regions involved in neural circuitry formation, projection, functioning, and plasticity. DNAm regions associated with MD where found to overlap genetic loci observed in the latest Psychiatric Genomics Consortium meta-analysis of depression. Understanding the time course of epigenetic influences during emerging adulthood may clarify developmental phases where genes modulate individual differences in MD risk.

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Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

et al. 2019

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Canonical Wnt signaling, which is transduced by β‐catenin and lymphoid enhancer factor 1/T cell‐specific transcription factors (LEF1/TCFs), regulates many aspects of metazoan development and tissue renewal. Although much evidence has associated canonical Wnt/β‐catenin signaling with mood disorders, the mechanistic links are still unknown. Many components of the canonical Wnt pathway are involved in cellular processes that are unrelated to classical canonical Wnt signaling, thus further blurring the picture. The present review critically evaluates the involvement of classical Wnt/β‐catenin signaling in developmental processes that putatively underlie the pathology of mental illnesses. Particular attention is given to the roles of LEF1/TCFs, which have been discussed surprisingly rarely in this context. Highlighting recent discoveries, we propose that alterations in the activity of LEF1/TCFs, and particularly of transcription factor 7‐like 2 (TCF7L2), result in defects previously associated with neuropsychiatric disorders, including imbalances in neurogenesis and oligodendrogenesis, the functional disruption of thalamocortical circuitry and dysfunction of the habenula.

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Neuregulin-1 and schizophrenia in the genome-wide association study era

Cited by 73 publications

References 194 publications

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ErbB and Toll-like receptor activation in first-episode schizophrenia

Twin Study of Early-Onset Major Depression Finds DNA Methylation Enrichment for Neurodevelopmental Genes

Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

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