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Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

2 May 2007. Genetic association and expression studies have implicated the neuregulin1 growth factor (NRG1) and its ErbB receptors, particularly ErbB4, in raising the risk of schizophrenia (Stefansson et al., 2002). A paper out May 1 in PNAS online from Gabriel Corfas and colleagues from Harvard Medical School in Boston, Massachusetts, adds substantial evidence to previous suggestions that defects in NRG1/ErbB4 signaling could underlie white matter defects in schizophrenia. The study finds that blocking NRG1/ErbB4 signaling in oligodendrocytes in mice causes a defect in myelination and slower nerve transmission in the brain. Other changes that they report, including enhanced dopaminergic signaling, decreased activity, impaired social interactions, and sensitivity to amphetamine, may model some of the manifestations of schizophrenia.

A second paper, led by the Icelandic company that originally linked neuregulin to schizophrenia, looks at how the loss of the NRG1/ErbB pathway affects neurons and synaptic function. In the April 25 Journal of Neuroscience, a research team led by Mark Gurney at deCODE Genetics in Reykjavik, Iceland, and their collaborators at Roche Palo Alto in California report that NRG1 regulates the function of NMDA-type glutamate receptors, thereby exerting a direct effect on neurotransmission through glutamatergic pathways, another locus of aberration in schizophrenia (see Current Hypothesis paper by B. Moghaddam).

Myelin matters
To find out if NRG1/ErbB signaling contributes to CNS myelination, and whether that might play a role in psychiatric disorders, joint first authors Kristine Roy and Joshue Murtie and the Harvard team created transgenic mice with a targeted block of ErbB signaling only in oligodendrocytes (OL), the cells that wrap CNS axons with myelin. The ErbB family of receptors features extracellular ligand binding domains linked to cytoplasmic tyrosine kinase signaling domains. Expression of a truncated receptor lacking the cytoplasmic domain has been shown to block signaling through endogenous receptors in a dominant negative fashion. By making transgenic mice with a truncated ErbB4 gene under control of an OL-specific promoter, the investigators produced mice that expressed the dominant negative protein only in OLs and their precursors. Because the truncated form can dimerize with other ErbB family members, Roy and colleagues detected inhibition of signaling not just through the ErbB4 receptor, but the related -B2 and -B3 receptors as well.

Since NRG1/ErbB was believed to be required to maintain the OL lineage, the investigators thought they might find fewer OLs in the transgenic mice, but that was not the case. OL number actually increased by 40 percent, but morphology was not abnormal. The cells were smaller, and their processes had fewer branches. These simplified, smaller OLs would be expected to cover less axon area, and indeed the researchers found thinner myelin sheaths in the optic nerve and the corpus callosum of transgenic mice.

In young mice, the changes in myelination resulted in slower nerve conduction speeds and changes in behavior. Transgenic mice explored in the open field less, displayed increased anxiety, and had abnormal social interactions. The mice were also hypersensitive to repeated doses of amphetamine, a sign of defects in dopamine function seen in schizophrenia. The researchers took a closer look at the dopamine system in the transgenic mice, and found that levels of dopamine transporters and dopamine receptor type 1-like binding increased in several regions of the brain. Moreover, stimulation with either a dopamine receptor agonist or amphetamine induced greater responses in gene expression, dopamine release, and behavioral measures than in control mice.

“Our findings indicate that defects in OL structure/function can cause alterations in neurotransmission that are relevant to psychiatric diseases,” the authors conclude. The study may help to resolve an outstanding question from NRG1/ErbB4 genetics work, that is, whether the loss of the pathway or a gain of function contributes to the features of schizophrenia. This study suggests a loss-of-function model for these genes. It also suggests that one lesion could contribute to both positive symptoms (as evidenced by increased sensitivity to amphetamines in this study) and negative ones (as evidenced by hypoactivity, and social withdrawal).

In a press release accompanying the paper, Corfas also speculated that the involvement of white matter could help explain why schizophrenia often sets in during adolescence or early adulthood, a time of active myelination of the prefrontal cortex.

NRG1 and neurons
The NRG1/ErbB pathway could contribute to some of the symptoms of schizophrenia through effects in neurons as well, says the second report. In that paper, the researchers show that interfering with NRG1 signaling (they use NRG1 or ErbB knockout mice) leads to reductions in NMDA receptor phosphorylation and changes in its function (see SRF related news story). Treatment with the atypical antipsychotic drug clozapine reversed the receptor hypophosphorylation and improved behavioral abnormalities in the mice. The results indicate that alterations in the NRG1/ErbB pathway and resulting alterations of NMDA receptor function might cause some of the pathophysiology of schizophrenia.

Joint first authors Maria Bjarnadottir and Dinah Misner started out looking for downstream effectors of the NRG1/ErbB4 pair. A yeast two-hybrid assay with the ErbB4 cytoplasmic tail and a mass spectrometry analysis of ErbB4 protein complexes immunoprecipitated from brain identified the cytoplasmic tyrosine kinases Fyn and Pyk2, respectively, as binding partners for the receptor. In cells overexpressing ErbB4 and Fyn, the researchers found that NRG1 caused Fyn activation.

Both kinases can phosphorylate a regulatory site on the NR2A subunit of the NMDA receptor, and the researchers determined that NRG1 treatment of human neuroblastoma cells resulted in an increase in NR2A phosphorylation at Y1472. Conversely, the same site is hypophosphorylated in either NRG1 or ErbB4 heterozygous knockout mice, suggesting the pathway functions in vivo.

Consistent with the idea that NRG1/ErbB4 regulates NMDA receptor activity, the knockout mice showed changes in some measures of synaptic plasticity. Depending on the stimulus, they had defects in LTP and changes in short-term synaptic plasticity. Treating hippocampal slices from NRG1+/- animals with exogenous neuregulin reversed some effects. The dose-response curves were complicated, suggesting that there may be an optimal level of NRG1 required for proper synapse formation.

The deCODE group previously showed that their NRG1+/- mice have behavioral abnormalities that could be reversed by treatment with clozapine (Stefansson et al., 2002). The current study extends this by showing that the same treatment also restores normal levels of NMDA receptor phosphorylation.

“These data suggest to us that NRG1-associated susceptibility to schizophrenia is at least partly associated with hypofunction of NRG1 signaling through ErbB4, Fyn, and other associated kinases such as Pyk2, that phosphorylate regulatory sites on NMDAR subunits, resulting in abnormal modulation of excitatory glutamatergic neurotransmission,” the authors write. These data are consistent, they say, with the glutamatergic hypothesis of schizophrenia, and studies implicating several other genes involved in glutamatergic signaling in the disease.

Both reports suggest potential new avenues for treatment, including restoring oligodendrocyte function by augmenting the NRG1/ErbB4 signaling pathway, or normalizing NMDA receptor phosphorylation and function.—Pat McCaffrey.

References:
Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM, Benoit-Marand M, Chen C, Moore H, O'Donnell P, Brunner D, Corfas G. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. 2007 May 1; PNAS Early Edition.

Bjarnadottir et al. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: Differential synaptic function in NRG+/- knock-outs compared with wild-type mice. J. Neurosci. 2007 April 25; 27:4519-4529. Abstract

 
Comments on News and Primary Papers
Comment by:  Daniel StewartKenneth Davis
Submitted 3 May 2007 Posted 3 May 2007

Comment by Daniel Stewart and Kenneth Davis
The Corfas results are intriguing. Their findings confirm much of what we have either found or suspect in schizophrenia relating to white matter involvement. Demonstrations of OLIG2 interactions with ErbB4 in the cortex and with CNP in the striatum in schizophrenia from our team (Georgieva et al., 2006) fit well with this investigation in providing evidence for a link between a variety of potential etiologic oligodendrocyte-related mechanisms in schizophrenia. While in our study, we did not find interaction with NRG1 and OLIG2, it is important to note that differential expression of NRG1 might be found only at certain points in the timeline of disease development. Other recent support from our team for white matter involvement in schizophrenia comes from an investigation in which an SNP associated with CNP was found to be significantly correlated with schizophrenia (Peirce et al., 2006). Interestingly, Corfas’s group reports that...  Read more


View all comments by Daniel Stewart
View all comments by Kenneth Davis

Comment by:  Akira Sawa, SRF Advisor
Submitted 4 May 2007 Posted 4 May 2007

Neuregulin1 (NRG1) is the most promising risk factor for schizophrenia, and the study of the signaling of NRG1 and its receptor ErbB4 is very important in understanding the pathophysiology of the disease. Like other promising risk factors for schizophrenia, NRG1/ErbB4 is multifunctional with many molecular isoforms. NRG1/ErbB signaling plays a role both before and after birth. Furthermore, ErbB4 is expressed not only in neurons but also in other types of cells, such as oligodendrocytes.

To address context-dependent functions one by one, dominant-negative transgenic mice can be very useful. The advantage of dominant-negative transgenics is that we can knock down the endogenous function of our target molecules (in this work, ErbB4) in a temporally and spatially specific manner by utilizing a well-characterized promoter. In this outstanding study by Corfas and colleagues, they used the CNP promoter that confirms dominant-negative ErbB4 selectively in oligodendrocytes (but not in astrocytes and neurons) only after birth. This approach will be very useful in schizophrenia...  Read more


View all comments by Akira Sawa

Comment by:  Mary Reid
Submitted 3 May 2007 Posted 5 May 2007

Does the effect of NRG1/ErbB4 signaling on myelination occur downstream of purinergic signaling? Fields suggests that adenosine is of primary importance in regulating early development of OPCs, where it stimulates differentiation and myelination (Fields, 2006). It's of interest that cAMP stimulates expression of neuregulin and cAMP levels in the lung are decreased in A2A adenosine receptor (22q11.2)-deficient mice (Tokita et al., 2001; Nadeem et al., 2007). Do you see reduced neuregulin levels in 22q11 deletion syndrome? Of particular interest is the study by Desai and colleagues reporting that signaling via the adenosine A2A receptor downregulates thrombospondin 1 (Desai et al., 2005). Perhaps overexpression of thrombospondin 1 may help explain the occular abnormalities in this syndrome (Wu et al., 2006; Forbes et al., 2007; Stalmans, 2005). Thrombospondins are also involved in synaptogenesis (Christopherson et al., 2005).

References:

Fields RD. Nerve impulses regulate myelination through purinergic signalling. Novartis Found Symp. 2006;276:148-58; discussion 158-61, 233-7, 275-81.

Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S, Oohira A. Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci. 2001 Feb 15;21(4):1257-64.

Nadeem A, Fan M, Ansari HR, Ledent C, Mustafa SJ. Enhanced airway reactivity and inflammation in A2A adenosine receptor deficient allergic mice. Am J Physiol Lung Cell Mol Physiol. 2007 Feb 9; [Epub ahead of print]

Desai A, Victor-Vega C, Gadangi S, Montesinos MC, Chu CC, Cronstein BN. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol. 2005 May;67(5):1406-13. Epub 2005 Jan 26. Comment in: Mol Pharmacol. 2005 May;67(5):1385-7.

Wu Z, Wang S, Sorenson CM, Sheibani N. Attenuation of retinal vascular development and neovascularization in transgenic mice over-expressing thrombospondin-1 in the lens. Dev Dyn. 2006 Jul;235(7):1908-20.

Forbes BJ, Binenbaum G, Edmond JC, Delarato N, McDonald-McGinn DM, Zackai EH. Ocular findings in the chromosome 22q11.2 deletion syndrome. J AAPOS. 2007 Apr;11(2):179-182. Epub 2006 Nov 30.

Stalmans I. Role of the vascular endothelial growth factor isoforms in retinal angiogenesis and DiGeorge syndrome. Verh K Acad Geneeskd Belg. 2005;67(4):229-76.

Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005 Feb 11;120(3):421-33. Comment in: Cell. 2005 Feb 11;120(3):292-3.

View all comments by Mary Reid


Comment by:  Patricia Estani
Submitted 6 May 2007 Posted 6 May 2007
  I recommend the Primary Papers
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