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Updated 24 February 2009 E-mail discussion
Printable version

Live Discussion: Neuregulin 1 Roundtable 2009

David Talmage

Amanda J. Law

View article

On Tuesday, 24 February, at 12 noon Eastern U.S. time, we hosted a live discussion of the state of the neuregulin 1 research as it may relate to schizophrenia. Amanda J. Law of the University of Oxford and National Institutes of Mental Health in Bethesda, Maryland, and David Talmage of the State University of New York, Stony Brook, touched on the dizzying array of isoforms and the many functions NRG1 is involved in from development through adult neurobiology.

In particular, Law and Talmage recommended these three papers for background reading:

Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006 Jul 15;60(2):132-40. Abstract

Role LW, Talmage DA. Neurobiology: new order for thought disorders. Nature. 2007 Jul 19;448(7151):263-5. Abstract

Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008 Jun 1;9(6):437-52. Abstract

You can download the PDF of Harrison and Law (2006) directly from the link beneath the photo above, courtesy of Biological Psychiatry and Elsevier.

View Transcript of Live Discussion — Posted 22 April 2009

View Comments By:
Richard Deth — Posted 29 January 2009
Malcolm Nason — Posted 23 February 2009
Timothy Crow — Posted 24 February 2009
Brian Dean — Posted 25 February 2009

Background Text
By Amanda Law and David Talmage

The association between genetic variation in NRG1 and schizophrenia (Stefansson et al., 2002) was greeted with substantial fanfare because of the known role of NRG1 signaling in the development of normal neuronal connectivity (see Harrison and Law, 2006; Role and Talmage, 2007). The NRG1 gene is complex: differential splicing coupled to utilization of at least six promoters generates mRNAs with the capacity to encode as many as 30 different proteins (Falls, 2003; Mei and Xiong, 2008). Different members of this family of signaling proteins utilize distinct and overlapping strategies for directing local cellular responses. As yet we do not have a clear picture of which aspects of NRG1 signaling are affected in the development of neuropsychiatric disorders such as schizophrenia, but emerging postmortem studies point towards altered levels of specific isoforms, perhaps resulting in aberrant ErbB4 activation and an imbalance between paracrine and juxtacrine signaling.

Of specific relevance to this discussion are recent findings linking changes in NRG1 signaling with perturbations of synaptic transmission, myelination, and the survival of particular sets of neurons and glia (Bjarnadottir et al., 2007; Michailov et al., 2004; Wolpowitz et al., 2000; Zhong et al., 2008). NRG1-ErbB signaling modulates activity dependent synaptic plasticity by regulating NMDA receptor levels and phosphorylation, by regulating AMPA and nicotinic acetylcholine receptor trafficking, and by regulating GABA release (Li et al., 2007; Woo et al., 2007; Chen et al., 2008). More recently NRG1 has been associated with dopaminergic signaling (Kwon et al., 2008). A fine balance of NRG1-ErbB signaling appears to be required: both deficient and excessive signaling interfere with synaptic plasticity. Given the apparent sensitivity of the NRG1-ErbB signaling to perturbations, it is becoming clearer how subtle changes in the levels and types of NRG1-ErbB interactions could alter the ability of key brain circuits to withstand additional genetic and environmental insults and contribute to disease.

Transcriptional regulation of NRG1 expression is likely to be important but is a largely underexplored area. Changes in NRG1 expression occur in pathological conditions, including injury to the nervous system. In addition, few of the DNA sequence changes in the NRG1 gene that are believed to confer susceptibility for schizophrenia alter protein structure. These non-coding polymorphisms are likely to alter the overall level of expression, the pattern and timing of expression, or the relative expression of different isoforms of NRG1, with the resulting changes in NRG1 protein levels contributing to the etiology of disease. Data consistent with this hypothesis include the finding of increases in the levels of type I mRNAs in postmortem brains from schizophrenia patients compared to controls (Hashimoto et al., 2004; Law et al., 2006) and of association of a functional promoter risk variant with type IV NRG1 levels (Law et al., 2006; Tan et al., 2007). The additional demonstration that reduced expression of subsets of Nrg1 isoforms in mice perturbs circuits underlying sensorimotor gating, memory performance, and synaptic functions relating to dopamine, GABA, glutamate, and acetylcholine underscores the point that altering the expression of NRG1 can contribute to pathology.

Based on this platform, the following points should be considered for this discussion:

1. The NRG1 gene: Complexity of splicing and isoform regulation.

2. Using animal and cellular models to investigate the biological role of NRG1 signaling during neurodevelopment and its role in adult brain function and pathology. The role of NRG1 signaling in the regulation of GABA, glutamate and cholinergic development and function.

3. Molecular mechanisms of NRG1 association. What the genetics has taught us about aberrant NRG1 gene regulation in schizophrenia.

4. Moving beyond NRG1. Thinking of NRG1 as part of a “disease pathway” based on association of other molecules in the signaling pathway to schizophrenia, i.e., ErbB receptors.

5. Where next for NRG1? Potential for therapeutic intervention?

Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Brynjolfsson J, Gunnarsdottir S, Ivarsson O, Chou TT, Hjaltason O, Birgisdottir B, Jonsson H, Gudnadottir VG, Gudmundsdottir E, Bjornsson A, Ingvarsson B, Ingason A, Sigfusson S, Hardardottir H, Harvey RP, Lai D, Zhou M, Brunner D, Mutel V, Gonzalo A, Lemke G, Sainz J, Johannesson G, Andresson T, Gudbjartsson D, Manolescu A, Frigge ML, Gurney ME, Kong A, Gulcher JR, Petursson H, Stefansson K. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002 Oct 1;71(4):877-92. Abstract

Harrison PJ, Law AJ. Neuregulin 1 and schizophrenia: genetics, gene expression, and neurobiology. Biol Psychiatry. 2006 Jul 15;60(2):132-40. Abstract

Role LW, Talmage DA. Neurobiology: new order for thought disorders. Nature. 2007 Jul 19;448(7151):263-5. Abstract

Falls DL. Neuregulins: functions, forms, and signaling strategies. Exp Cell Res. 2003 Mar 10;284(1):14-30. Abstract

Mei L, Xiong WC. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008 Jun 1;9(6):437-52. Abstract

Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H, Sigmundsson A, Firth DR, Nielsen B, Stefansdottir R, Novak TJ, Stefansson K, Gurney ME, Andresson T. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: differential synaptic function in NRG1+/- knock-outs compared with wild-type mice. J Neurosci. 2007 Apr 25;27(17):4519-29. Abstract

Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, Nave KA. Axonal neuregulin-1 regulates myelin sheath thickness. Science. 2004 Apr 30;304(5671):700-3. Abstract

Wolpowitz D, Mason TB, Dietrich P, Mendelsohn M, Talmage DA, Role LW. Cysteine-rich domain isoforms of the neuregulin-1 gene are required for maintenance of peripheral synapses. Neuron. 2000 Jan 1;25(1):79-91. Abstract

Zhong C, Du C, Hancock M, Mertz M, Talmage DA, Role LW. Presynaptic type III neuregulin 1 is required for sustained enhancement of hippocampal transmission by nicotine and for axonal targeting of alpha7 nicotinic acetylcholine receptors. J Neurosci. 2008 Sep 10;28(37):9111-6. Abstract

Li B, Woo RS, Mei L, Malinow R. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron. 2007 May 24;54(4):583-97. Abstract

Woo RS, Li XM, Tao Y, Carpenter-Hyland E, Huang YZ, Weber J, Neiswender H, Dong XP, Wu J, Gassmann M, Lai C, Xiong WC, Gao TM, Mei L. Neuregulin-1 enhances depolarization-induced GABA release. Neuron. 2007 May 24;54(4):599-610. Abstract

Chen YJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S, Lewandowski N, Rosoklija G, Liu RC, Gingrich JA, Small S, Moore H, Dwork AJ, Talmage DA, Role LW. Type III neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and corticostriatal circuit components. J Neurosci. 2008 Jul 2;28(27):6872-83. Abstract

Kwon OB, Paredes D, Gonzalez CM, Neddens J, Hernandez L, Vullhorst D, Buonanno A. Neuregulin-1 regulates LTP at CA1 hippocampal synapses through activation of dopamine D4 receptors. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15587-92. Abstract

Hashimoto R, Straub RE, Weickert CS, Hyde TM, Kleinman JE, Weinberger DR. Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. Mol Psychiatry. 2004 Mar 1;9(3):299-307. Abstract

Law AJ, Lipska BK, Weickert CS, Hyde TM, Straub RE, Hashimoto R, Harrison PJ, Kleinman JE, Weinberger DR. Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6747-52. Abstract

Tan W, Wang Y, Gold B, Chen J, Dean M, Harrison PJ, Weinberger DR, Law AJ. Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia. J Biol Chem. 2007 Aug 17;282(33):24343-51. Abstract

Comments on Online Discussion
Comment by:  Richard Deth
Submitted 28 January 2009 Posted 29 January 2009

The alternative splicing of neuregulin-1 is only one of many examples in the brain (BDNF, etc.), and it appears that alternative splicing is more common in the brain than in other tissues. It may, therefore, be useful to also consider the mechanism of alternative mRNA splicing of neuregulin-1 as a candidate process which may underlie schizophrenia. In other words, if the factors regulating alternative splicing functioned abnormally, it would influence a broad number of gene products. SNPs or mutations in these genes would represent a second source of vulnerability.

View all comments by Richard Deth

Comment by:  Malcolm Nason
Submitted 23 February 2009 Posted 23 February 2009

Considering the strong influence of puberty on the development of schizophrenia, how do you think that Neuregulin affects this process? I am particularly interested in the "chicken and egg" problem, so to speak, since Nrg has direct effects on development of tissues which induce and influence puberty itself. Could a better regulated puberty (if such a thing were possible, say through exogenous hormone treatments) reduce the influence of aberrant Nrg?

View all comments by Malcolm Nason

Comment by:  Timothy Crow
Submitted 24 February 2009 Posted 24 February 2009

With respect to my colleagues in the Oxford Department, whose technical expertise I do not doubt, this question surely reflects the quagmire into which psychosis genetics has now fallen.

1. Neuregulin came into prominence in this field with the paper by Stefannson et al. (Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877-892) who reported a multipoint lod score of 3.06 on chromosome 8p in 33 families.

Much larger linkage surveys are now available and they do not support this finding. I reviewed three whole genome scans (the largest, each n >300 pairs) on a total of 1,144 sibling pairs with schizophrenia or schizoaffective disorder (Crow TJ. How and why genetic linkage has not solved the problem of psychosis: review and hypothesis. Am J Psychiatry 2007; 164: 13-21). Only one of these studies showed a lod peak on chromosome 8 above 1.5 (Suarez et al. Genome-wide linkage scan of 409 European-ancestry and African American families with schizophrenia: suggestive evidence of linkage at 8p23.3-p21.2 and 11p13.1-q14.1 in the combined sample. Am J...  Read more

View all comments by Timothy Crow

Comment by:  Brian Dean
Submitted 25 February 2009 Posted 25 February 2009

If we consider other disorders that were first diagnosed on symptom profile presentation, such as diabetes, renal diseases, and congenital heart diseases, it is very likely that the diagnosis of schizophrenia as it is currently used defines a syndrome of disorders. The fact that a significant proportion of subjects with schizophrenia are resistant to antipsychotic drug treatment and therefore probably do not have a dopamine-related disorder clearly supports the notion of schizophrenia as a syndrome. Therefore, in considering any gene as a candidate gene, it must be asked whether it is likely that any gene could strongly associate with a syndrome. This would seem very unlikely as syndromes are usually made up of different disorders that each have unique pathophysiologies.

Debates on the roles of molecules should not get bogged down in whether or not the gene for that molecule is a "candidate" gene for schizophrenia. Rather, they should focus on whether the biology of the molecule could implicate it in the pathophysiology of the symptoms of schizophrenia. NRG1 would seem to...  Read more

View all comments by Brian Dean
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