Neuregulin-1 (<i>NRG1</i>) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia

Bousman, Chad; Cropley, Vanessa; Klauser, Paul; Hess, Jonathan; Pereira, Avril; Idrizi, Rejhan; Bruggemann, Jason; Mostaid, Shaki; Lenroot, R.; Weickert, Thomas W.; Glatt, Stephen J.; Everall, Ian; Sundram, Suresh; Zalesky, Andrew; Weickert, Cynthia Shannon; Pantelis, Christos

doi:10.1017/s0033291717002173

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…A recent study indicated that mice with a subtle defect of myelination could exhibit the schizophrenia-like symptoms (31). In the past decade, there is growing evidence from imaging (32), genetic (33, 34), and postmortem (35, 36) studies that white matter impairment plays an important role in the pathogenesis of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Low Field Magnetic Stimulation Ameliorates Schizophrenia-Like Behavior and Up-Regulates Neuregulin-1 Expression in a Mouse Model of Cuprizone-Induced Demyelination

Sun

Jiang

et al. 2018

Front. Psychiatry

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White matter and myelin sheath integrity are disrupted in schizophrenia, and non-invasive magnetic brain stimulation targeting these tracts is a promising new therapeutic approach. In particular, deep-brain reachable low field magnetic stimulation (DMS) could alleviate cognitive impairment and depressive-like behaviors in animal models. In this study, we sought to assess the effects of DMS on myelin sheath damage and schizophrenia-like behaviors in the cuprizone-induced demyelination mouse model. Mice were fed cuprizone (copper ion chelating agent, 0.2% w/w mixed with food) for 6 weeks to induce demyelination. During these 6 weeks, mice were stimulated with either sham, low-frequency (LFS, delta frequency) DMS or high-frequency (HFS, gamma Hz) DMS for 20 min each day. Behavioral tests were conducted 24 h after the final DMS session. The myelin sheath was examined by immunohistochemistry and the expression of neuregulin-1 (NRG1)/ErbB4 in the prefrontal cortex was measured with Western blotting. Six weeks of HFS significantly alleviated schizophrenia-like behaviors in cuprizone mice, including improved nesting, social interaction and sensorimotor gating, while LFS improved sensorimotor gating only. HFS and LFS both repaired the myelin sheath and increased the expression of neuregulin-1 and its receptor ErbB4, in the prefrontal cortex of demyelinated mice. Our findings show that DMS is a potential effective neuromodulation technique for the treatment of schizophrenia. One possible mechanism underlying these therapeutic effects could involve the up-regulation of NRG1/ErbB4 signaling in the prefrontal cortex.

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Section: Discussionmentioning

confidence: 99%

Low Field Magnetic Stimulation Ameliorates Schizophrenia-Like Behavior and Up-Regulates Neuregulin-1 Expression in a Mouse Model of Cuprizone-Induced Demyelination

Sun

Jiang

et al. 2018

Front. Psychiatry

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“…Signaling deficits in NRG1/ErbB3 has been identified in schizophrenia patients ( Corfas et al, 2004 ). Single nucleotide polymorphisms in NRG1; have been associated with psychosis and enlarged lateral ventricles and white matter disruption in schizophrenia ( Bousman et al, 2018 ). Another important mediator between microglia and neuron communication is BDNF, where microglia is one of the central source of BDNF ( Ferrini and De Koninck, 2013 ).…”

Section: Schizophreniamentioning

confidence: 99%

Bidirectional Microglia–Neuron Communication in Health and Disease

Szepesi

Manouchehrian²,

Bachiller³

et al. 2018

Front. Cell. Neurosci.

358

293

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Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult to the CNS homeostasis. Although microglia have long been recognized as a crucial player in generating and maintaining inflammatory responses in the CNS, now it has become clear, that their function are much more diverse, particularly in the healthy brain. The innate immune response and phagocytosis represent only a little segment of microglia functional repertoire that also includes maintenance of biochemical homeostasis, neuronal circuit maturation during development and experience-dependent remodeling of neuronal circuits in the adult brain. Being equipped by numerous receptors and cell surface molecules microglia can perform bidirectional interactions with other cell types in the CNS. There is accumulating evidence showing that neurons inform microglia about their status and thus are capable of controlling microglial activation and motility while microglia also modulate neuronal activities. This review addresses the topic: how microglia communicate with other cell types in the brain, including fractalkine signaling, secreted soluble factors and extracellular vesicles. We summarize the current state of knowledge of physiological role and function of microglia during brain development and in the mature brain and further highlight microglial contribution to brain pathologies such as Alzheimer’s and Parkinson’s disease, brain ischemia, traumatic brain injury, brain tumor as well as neuropsychiatric diseases (depression, bipolar disorder, and schizophrenia).

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“… 36 It has been linked to NRG1 risk variants in first-episode schizophrenia patients 37 and in individuals at high risk for psychosis. 38 We reported enlarged lateral ventricles in transgenic mice with CRD-NRG1 overexpression. 14 Here, we confirm increased ventricular size in T-Nrg1 mice, demonstrating ventricular enlargement as a specific outcome of hyperactive CRD-NRG1 signaling.…”

Section: Discussionmentioning

confidence: 79%

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks

Götze

Soto-Bernardini

Zhang

et al. 2021

Schizophrenia Bulletin

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The neuregulin 1 (NRG1) ErbB4 module is at the core of an “at risk” signaling pathway in schizophrenia. Several human studies suggest hyperstimulation of NRG1-ErbB4 signaling as a plausible pathomechanism; however, little is known about the significance of stage-, brain area-, or neural cell type-specific NRG1-ErbB4 hyperactivity for disease-relevant brain endophenotypes. To address these spatiotemporal aspects, we generated transgenic mice for Cre recombinase-mediated overexpression of cystein-rich domain (CRD) NRG1, the most prominent NRG1 isoform in the brain. A comparison of “brain-wide” vs cell type-specific CRD-NRG1 overexpressing mice revealed that pathogenic CRD-NRG1 signals for ventricular enlargement and neuroinflammation originate outside glutamatergic neurons and suggests a subcortical function of CRD-NRG1 in the control of body weight. Embryonic onset of CRD-NRG1 in glutamatergic cortical networks resulted in reduced inhibitory neurotransmission and locomotor hyperactivity. Our findings identify ventricular enlargement and locomotor hyperactivity, 2 main endophenotypes of schizophrenia, as specific consequences of spatiotemporally distinct expression profiles of hyperactivated CRD-NRG1 signaling.

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Neuregulin-1 (NRG1) polymorphisms linked with psychosis transition are associated with enlarged lateral ventricles and white matter disruption in schizophrenia

Abstract: Our findings build on a growing body of research supporting the functional importance of genetic variation within the NRG1 gene and complement previous findings implicating the rs4281084 and rs12155594 SNPs as markers for psychosis transition.

Cited by 10 publications

References 32 publications

Low Field Magnetic Stimulation Ameliorates Schizophrenia-Like Behavior and Up-Regulates Neuregulin-1 Expression in a Mouse Model of Cuprizone-Induced Demyelination

Low Field Magnetic Stimulation Ameliorates Schizophrenia-Like Behavior and Up-Regulates Neuregulin-1 Expression in a Mouse Model of Cuprizone-Induced Demyelination

Bidirectional Microglia–Neuron Communication in Health and Disease

Hyperactivity is a Core Endophenotype of Elevated Neuregulin-1 Signaling in Embryonic Glutamatergic Networks

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