Adapted from a story that originally appeared on the Schizophrenia Research Forum.

3 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 evidence to previous suggestions that defects in NRG1/ErbB4 signaling could underlie white matter defects. 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 in these mice, including enhanced dopaminergic signaling, decreased activity, impaired social interactions, and sensitivity to amphetamine, may model some 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, researchers led by Mark Gurney at deCODE Genetics in Reykjavik, Iceland, with 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.

Both studies are primarily relevant to schizophrenia, but the emerging area of neuregulin signaling bears watching for AD researchers, as well, because the underlying mechanisms suggest areas of overlap. For one, degeneration of white matter tracts is a common, if poorly understood, observation in brain imaging of AD. For another, neuregulin is a physiological substrate of the β-secretase BACE, which also processes APP. At the 8th International conference AD/PD, held this past March in Salzburg, Austria, Christian Haass of Ludwig-Maximilians University, Munich, extended to the CNS his group’s prior findings of peripheral demyelination in BACE knockout mice (Willem et al., 2006). At the conference, Haass reported that crossing the BACE knockout mice with neuregulin knockdown mice, a genetic manipulation to further reduce BACE processing and neuregulin signaling, caused hypomyelination in the brain, as well. This indication for a genetic interaction between BACE and neuregulin in brain reinforces the message that AD drug development efforts using BACE inhibitors would do well to understand BACE and neuregulin biology in depth.

Myelin Matters
To find out if NRG1/ErbB signaling contributes to CNS myelination, first author Kristine Roy 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. The number of OLs actually grew by 40 percent, but the cells were smaller, and their processes had fewer branches. These simplified 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.

Young transgenic mice exhibited 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. The researchers found that levels of dopamine transporters and dopamine receptor type 1-like binding were increased in several regions of the mice’s brain. 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 the heightened sensitivity to amphetamines in this study) and negative ones (as evidenced by passivity and social withdrawal). In a press release accompanying the paper, Corfas 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. George Bartzokis has previously linked the onset of neurodegeneration to the order by which brain areas become myelinated during a person’s growth and maturation Bartzokis et al., 2006; Bartzokis et al., 2004).

NRG1 and Neurons
The NRG1/ErbB pathway could contribute to psychotic symptoms through effects in neurons as well, says the second report. These researchers show that interfering with NRG1 signaling by using NRG1 or ErbB knockout mice leads to reductions in NMDA receptor phosphorylation and changes in its function (see Schizophrenia Research Forum related news story). Treatment with the atypical antipsychotic drug clozapine restored receptor phosphorylation and improved behavioral abnormalities in the mice. 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, NRG1 caused Fyn activation. Fyn has already been implicated in synaptic alterations in AD mouse models (see Chin et al., 2005).

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 defects in some measures of synaptic plasticity, including LTP. Treating hippocampal slices from NRG1+/- animals with exogenous neuregulin reversed some effects. The dose-response curves were complicated, suggesting that an optimal level of NRG1 may be required for proper synapse formation. The NR2A subunit is drawing increasing interest in several neurologic diseases, and has most recently been implicated in anxiety in AD (e.g., Tsang et al., 2007).

The deCODE group previously showed that their NRG1+/- mice have behavioral abnormalities that were 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 and Gabrielle Strobel

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References

Paper Citations

  1. . Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet. 2002 Oct;71(4):877-92. PubMed.
  2. . Control of peripheral nerve myelination by the beta-secretase BACE1. Science. 2006 Oct 27;314(5799):664-6. PubMed.
  3. . Apolipoprotein E genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. Arch Gen Psychiatry. 2006 Jan;63(1):63-72. PubMed.
  4. . Heterogeneous age-related breakdown of white matter structural integrity: implications for cortical "disconnection" in aging and Alzheimer's disease. Neurobiol Aging. 2004 Aug;25(7):843-51. PubMed.
  5. . Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci. 2005 Oct 19;25(42):9694-703. PubMed.
  6. . Alterations in NMDA receptor subunit densities and ligand binding to glycine recognition sites are associated with chronic anxiety in Alzheimer's disease. Neurobiol Aging. 2008 Oct;29(10):1524-32. PubMed.

External Citations

  1. Schizophrenia Research Forum
  2. NRG1
  3. ErbB4
  4. press release
  5. Schizophrenia Research Forum related news story

Further Reading

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Primary Papers

  1. . 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. PubMed.
  2. . Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8131-6. PubMed.