Neuregulins and Neuronal Plasticity: Possible Relevance in Schizophrenia

Buonanno, Andrés; Kwon, Oh‐Bin; Yan, Leqin; González, Carmen; Longart, Marines; Hoffman, Dax A.; Vullhorst, Detlef

doi:10.1002/9780470751251.ch13

Cited by 18 publications

(16 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Haplo-insufficiency of Nrg1 or ErbB4 has been suggested to cause schizophrenia [4,39,40]. Consistent with this notion, reduced activity of the Akt/GSK3β pathway has also been linked to schizophrenia [41].…”

Section: Discussionmentioning

confidence: 93%

Reversible Overexpression of Bace1-Cleaved Neuregulin-1 N-Terminal Fragment Induces Schizophrenia-Like Phenotypes in Mice

Luo

et al. 2014

Biological Psychiatry

View full text Add to dashboard Cite

Background Neuregulin-1 (Nrg1) is a pleiotropic signaling molecule that regulates neural development and mutation of Nrg1 is a risk factor for schizophrenia. Cleavage of type I β1 Nrg1 isoform by BACE1 releases a secreted N-terminal fragment (Nrg1-ntfβ), which can bind to a cognate ErbB receptor to activate the specific signaling cascade. This study aimed to determine whether increased expression of Nrg1 is beneficial for brain development and functions. Methods We generated transgenic mice overexpressing this fragment under the control of a tetracycline-inducible promoter and examined functional and behavioral changes in mice upon reversible expression of the transgene. Results Increased expression of full length Nrg1 in mouse neurons has been previously shown to enhance myelination in the central nervous system. Overexpressing Nrg1-ntfβ enhanced the expression of myelin proteins, consistent with the expected activation of the Nrg1 signaling pathway by Nrg1-ntfβ. Contrary to expectations, overexpressing Nrg1-ntfβ transgene caused schizophrenia-like behaviors in transgenic mice and these abnormal behaviors were reversible if the expression of the Nrg1-ntfβ transgene was turned off. Our molecular assay suggests that protein levels of NMDA receptors (NMDARs) are reduced in this transgenic mouse model, which may underlie the observed social and cognitive behavioral impairments. Conclusion Our results indicate that overexpressing the secreted form of Nrg1 is sufficient to cause schizophrenia-like behaviors in a mouse model, meaning the effect is independent of the transmembrane and C-terminal domains of Nrg1. Hence, genetic gain-of-function mutations of Nrg1 are also risk factors for schizophrenia.

show abstract

Section: Discussionmentioning

confidence: 93%

Reversible Overexpression of Bace1-Cleaved Neuregulin-1 N-Terminal Fragment Induces Schizophrenia-Like Phenotypes in Mice

Luo

et al. 2014

Biological Psychiatry

View full text Add to dashboard Cite

show abstract

“…Alternative promoter usage of the NRG1 gene gives rise the different NRG1 “types” and among these NRG1 types I through IV have been the most widely studied (see (72, 85, 88)). Three promoters were originally identified in the NRG1 gene that generate type I (ARIA, NDF, heregulin), type II (GGF) and type III (SMDF, CRD); refer to Fig.…”

Section: Introductionmentioning

confidence: 99%

“…(3–5);133–135)). NRG1 regulates distinct aspects of neural determination and differentiation in the peripheral and central nervous system, affecting neuronal and glial fate, migration, differentiation and maturation; this has been the subject of numerous reviews (85–88, 136, 137). Because the multitude of glial and neuronal functions regulated by the NRG-ErbB signaling are beyond the focus of this review, I will focus on neuronal migration, synaptic transmission and plasticity, and neural network activity because these are the processes most relevant to schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

The neuregulin signaling pathway and schizophrenia: From genes to synapses and neural circuits

Buonanno

2010

Brain Research Bulletin

Self Cite

152

127

View full text Add to dashboard Cite

Numerous genetic linkage and association studies implicate members of the Neuregulin-ErbB receptor (NRG-ErbB) signaling pathway as schizophrenia "at risk" genes. An emphasis of this review is to propose plausible neurobiological mechanisms, regulated by the Neuregulin-ErbB signaling network, that may be altered in schizophrenia and contribute to its etiology. To this end, the distinct neurotransmitter pathways, neuronal subtypes and neural network systems altered in schizophrenia are initially discussed. Next, the review focuses on the possible significance of genetic studies associating NRG1 and ErbB4 with schizophrenia, in light of the functional role of this signaling pathway in regulating glutamatergic, GABAergic and dopaminergic neurotransmission, as well as modulating synaptic plasticity and gamma oscillations. The importance of restricted ErbB4 receptor expression in GABAergic interneurons is emphasized, particularly their expression at glutamatergic synapses of parvalbumin-positive fast spiking interneurons where modulation of inhibitory drive could account for the dramatic effects of NRGErbB signaling on gamma oscillations and pyramidal neuron output. A case is made for reasons that the NRG-ErbB signaling pathway constitutes a "biologically plausible" system for understanding the pathogenic mechanisms that may underlie the complex array of positive, negative and cognitive deficits associated with schizophrenia during development.

show abstract

“…Several investigators have provided excellent reviews on genetic, neurobiological, and pathophysiologic studies of neuregulin 1 and erbB4 in schizophrenia [38–41]. In this article, we will evaluate the pathophysiologic evidence for NRG1 –erbB4 signaling with respect to its interactions with other factors and will consider a putative interactome with which NRG1 – erbB4 signaling is associated.…”

Section: Introductionmentioning

confidence: 99%