Schizophrenia Research Forum - A Catalyst for Creative Thinking

Neuregulin, ErbB4—Levels Normal but Signaling Strengthened in Schizophrenia

18 June 2006. Finding a link between a disease and one of the 30,000 or so human genes is one thing, but finding that the disease is linked to two genes that code for interacting proteins seems highly significant, because it pinpoints a specific biological pathway that might be involved in pathology. So when researchers recently found that variations in the gene for the kinase ErbB4 increase the risk for schizophrenia only when they are inherited together with specific variants of the neuregulin 1 (NRG1) gene, it strengthened the case for dysfunctional NRG1-ErbB4 signaling in the disease (see SRF related news story). But despite this, and numerous reports linking neuregulin polymorphisms to schizophrenia (see SRF related news story), no consensus has emerged as to how the NRG1-ErbB4 signaling pathway might be disrupted. The main stumbling block seems to be that those genetic variations, which lie outside the coding region of the genes, have inconsistent, or very subtle, effects on mRNA and protein levels (see SRF related news story). But in the June 12 Nature Medicine online, researchers led by Chang-Gyu Hahn, University of Pennsylvania, Philadelphia, reported that NRG1-ErbB4 signal may, in fact, be altered in schizophrenia patients, even though levels of the two proteins appear normal.

Hahn, together with joint first author and Hoau-Yan Wang and colleagues, tested the neuregulin-ErbB4 pathway by challenging postmortem brain slices with exogenous NRG1, then measuring ErbB4 signaling in extracts prepared so that protein-protein interactions are maintained. Though the authors admit that it is unclear how such measurements relate to what goes on in vivo, they found significant differences between brain samples taken from people who had had schizophrenia and those who had not.

The first difference the authors noted was in activation of ErbB4 itself. Despite the fact that levels of NRG1 and ErbB4 were no different between prefrontal cortex (PFC) slices from schizophrenia patients and matched control samples, the authors found that on addition of exogenous NRG1, twice as much phosphorylated ErbB4 could be detected in PFC slices from schizophrenia subjects. Phosphorylation of the downstream kinases Erk-2 and Akt was also increased relative to control samples, though only slightly.

Why exogenous NRG1 should enhance ErbB4 signaling in schizophrenia brain samples is uncertain, but the downstream effects seem related to one of the major schizophrenia hypotheses, namely that the brain suffers from lack of N-methyl-D-aspartate receptor (NMDAR) activity (see glutamate hypothesis paper by Bita Moghaddam). When the authors stimulated PFC slices with NMDA they found classic signs of NMDAR activation, including increased phosphorylation of subunit 2A of the receptor and recruitment of phosphatidyl inositol phospholipase C-γ1 (PIPLC-γ1) by the NMDAR1 subunit. However, in PFC slices from postmortem schizophrenia brain, both these telltale modifications were significantly lower than in control tissue. The addition of NRG1 attenuated NMDAR activation even further. The latter effect may be related to increased coupling of ErbB4 to postsynaptic density 95 (PSD-95), a synapse protein that has a crucial role in activation of ErbB4 because though the authors found that PSD-95 levels in schizophrenia PFC samples were normal, much more of the protein coimmunoprecipitated with ErbB4 in schizophrenia samples than from control samples. “Our observation that the ErbB4-PSD-95 association was distinctly increased in schizophrenia, with PSD-95 protein levels unaltered, highlights the protein-protein interactions of PSD-95 as a potentially important mode of dysregulation in this disorder,” write the authors.

Though there is accumulating evidence that supports the NMDAR hypofunction hypothesis, “to our knowledge, this is the first evidence of decreased NMDA receptor function in postmortem brains from schizophrenia individuals,” write the authors about their findings. While dysfunctional NRG1-ErbB4 signaling could undoubtedly explain poor NMDAR activity, it is still unclear how non-coding polymorphisms in the two genes may increase the risk for the disease. Nonetheless, these latest findings add weight to both the NRG1-ErbB4 link and to the NMDAR hypothesis.—Tom Fagan.

Reference:
Hahn C-G, Wang H-Y, Cho D-S, Talbot K, Gur RE, Berrettini WH, Bakshi K, Kamins J, Borgmann-Winter KE, Siegel SJ, Gallop RJ, Arnold SE. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nature Medicine. June 12, 2006, advanced online publication. Abstract

Comments on News and Primary Papers
Comment by:  Patricia Estani
Submitted 22 June 2006
Posted 22 June 2006
  I recommend the Primary PapersComment by:  Cynthia Shannon Weickert, SRF AdvisorVictor Chong
Submitted 8 August 2006
Posted 8 August 2006

In contrast to its once barren form, the table of potential causative genes for schizophrenia is now stocked to feast level (Straub and Weinberger, 2006). In keeping with the culinary theme, we suggest that this recent paper by Chang-Gyu Hahn and Hoau-Yan Wang is “a full course meal”!

Appetizer: An Important Biological Problem
If one assumes that alterations in NRG-1 account for at least some of the liability to developing schizophrenia, then it is only reasonable to look to the NRG-1 receptors for clues as to how and where NRG-1 may be acting. However, there are three known NRG-1 receptors that mediate a myriad of biological functions, almost all of which could be argued to be relevant to schizophrenia pathology. This paper draws our attention to one NRG-1 receptor, ErbB4, showing this receptor to be a probable NRG-1 partner in mediating this pathology. Recent studies provide further support that ErbB4 may be integral to the development of schizophrenia by demonstrating its gene to be a potential susceptibility gene (Norton et al., 2006; Silberberg et al., 2006; Nicodemus et al., in press). So, genetic and neurobiological evidence suggest the authors selected their NRG-1 receptor wisely.

Main Course: A New Approach
The novel postmortem-stimulation approach used by Hahn and colleagues represents an important advance in the field of schizophrenia research. Through extensive validation of this protocol, this research group has paved the way for future experimentation into the molecular activation of proteins within the schizophrenic brain. More specifically, while previous studies have only been able to draw conclusions about the static state of the schizophrenic brain, this article has introduced a novel method for examining dynamic signaling systems in postmortem brains of patients with schizophrenia. For example, based on the finding that certain splice variant ErbB4 mRNAs are elevated in the prefrontal cortex of these individuals (Silberberg et al., 2006), one would assume that ErbB4 protein should also be elevated in these patients. But Hahn et al. demonstrate that schizophrenic individuals show only marginal increases in prefrontal cortical ErbB4 protein levels, which could suggest that ErbB4 protein plays little role in the pathology of schizophrenia. However, using the more dynamic postmortem-stimulation approach, the authors showed that ErbB4 signaling is, in fact, greatly enhanced in the prefrontal cortex of patients with this disease, leading to the alternative interpretation that ErbB4 protein may play significant roles in schizophrenia. In other words, this postmortem-stimulation protocol extends the examination of human postmortem brain protein from quantification to the functional level. We view this method as a powerful approach that will be important in translating genetic susceptibility into molecular mechanisms of the disease process. The postmortem-stimulation approach also gave rise to the observation that schizophrenic patients exhibit reduced prefrontal cortical NMDA receptor signaling capacity. This finding is highly significant because it is the first evidence directly linking reduced prefrontal cortical NMDA receptor function to schizophrenia. However, whether NRG-1-ErbB4 signaling is a major contributor to NMDA receptor hypofunction is debatable since the attenuation of NMDA receptor phosphorylation by NRG-1 appears proportionally similar between controls and schizophrenic patients.

Side Dish: Dealing with Antipsychotic Drugs
Since most patients with schizophrenia have received antipsychotic drugs and these agents can have profound impact on brain systems, it is essential to determine whether changes observed in the brains of patients with schizophrenia are secondary to antipsychotic drug exposure. To address this issue, the authors took two important steps. Firstly, Hahn et al. examined whether antipsychotic drug exposure affected prefrontal cortical ErbB4 expression or signaling in their human study group and found no correlation between antipsychotic drug treatment and either of these measured variables. Secondly, the authors examined antipsychotic drug effects on prefrontal cortical ErbB4 signaling in mice implanted with a haloperidol-containing bioabsorbable polymer, which has a number of advantages. For example, it allows for long-term treatment of the animals (12 weeks) while minimizing handling. This duration of exposure is arguably more appropriate than some schedules used to examine chronic effects of antipsychotic drugs in rodents. Remarkably, haloperidol treatment caused a reduction in ErbB4 signaling in the mice, suggesting that a decrease in ErbB4 signaling is associated with the therapeutic effects of antipsychotic agents. What may have been more informative is to show whether haloperidol had any effect on ErbB4 protein levels without NRG-1 treatment. In addition, the authors could have considered examining antipsychotic drug effect in mice whose ages were more reflective of those of the investigated human cohort, which consisted of elderly individuals (65-92 years). Furthermore, while their analysis of antipsychotic drugs on ErbB4 expression and signaling in postmortem brain was noteworthy, the authors only examined the effects of antipsychotic drugs taken in the final month before death in a very aged sample population. Thus, it is difficult to ascertain whether ErbB4 expression or signaling is not affected by lifetime antipsychotic drug treatment, which can result in cellular and molecular consequences that can remain long after termination of therapy.

Dessert: Challenging the Field
Of course, the first thing the field needs to do is attempt to replicate these findings in another cohort of patients with schizophrenia compared to controls. Careful attention to matching for age, PMI, and gender, etc., as was done in this study, is critical. We suggest that using a young cohort of patients would help rule out potential confounds such as associated dementia and interaction with the aging process. However, it is recognized that many other potential confounds will still remain in most studies comparing schizophrenics to unaffected controls. These confounds include suffering from years of an unremitting illness that compromises normal social and environmental stimulation, increased incidence of cigarette smoking among patients with schizophrenia, and years of antipsychotic drug exposure. When the finding of schizophrenia-associated increased ErbB4 signaling capacity is replicated, then the task at hand will be to determine how possible genetic changes in the DNA at the NRG-1 or ErbB4 locus (representing one etiological route) could lead to a “hyperactivatable” ErbB4.

Doggie Bag: Nagging Questions
One of the caveats we would like to raise in attempting to link molecular neurobiological changes found in schizophrenic brain tissue with possible changes in DNA is that causative variants in any one susceptibility gene are expected to occur only in a minority of schizophrenic patients. Most measures performed on postmortem schizophrenic brains are made on small sample sizes, which likely show much heterogeneity in terms of etiology. In other words, only a handful of patients in this study would be expected to have a faulty NRG-1 gene; yet this subpopulation shows alterations in ErbB4 signaling as a group. The logical extension of this observation may be that there are multiple routes by which ErbB4 could be “hyperactivatable” (i.e., not solely through NRG-1 genetic liability). To sort this out, we need to work from the gene forward, and thus there is a need to identify causative variants in susceptibility genes and to use these as starting points for basic mechanistic molecular and cellular studies.

View all comments by Cynthia Shannon Weickert
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Comments on Related News


Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Akira Sawa, SRF Advisor
Submitted 22 August 2006
Posted 22 August 2006

Many linkage analyses have reproducibly reported 8p21-22 as a linkage hot locus for schizophrenia. The gene coding for neuregulin-1 is regarded as a factor that contributes to the linkage peak, but other genes may also be involved. Dr. Gurling and colleagues have conducted an excellent association study and obtained evidence that the gene coding for pericentriolar material 1 (PCM1) is associated with schizophrenia.

The results from the genetic portions of this are consistent with our unpublished biological study. (The abstract of Kamiya et al. has been submitted to SFN meeting at Atlanta in October 2006.) In exploring protein interactors of disrupted-in-schizophrenia-1 (DISC1), a promising risk factor for schizophrenia and bipolar disorder, we already came across PCM1 as a potential protein interactor of DISC1. This interaction has been confirmed by yeast two-hybrid and biochemical methods. In immunofluorescent cell staining, a pool of DISC1 and PCM1 are co-stained at the centrosome. Therefore, this genetic study is really encouraging us to move beyond our preliminary study on DISC1 and PCM1.

Of interest, Gurling and colleagues reported in the paper that the cases with the PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. This may be in accordance with our previous publication (Sawamura et al., 2005) reporting the alteration in subcellular distribution of DISC1 in the orbitofrontal cortex of the patients with schizophrenia.

Although a possible link of DISC1 and PCM1 in the pathophysiology of schizophrenia is still hypothetical, the intriguing work by Dr. Gurling and colleagues may now open a window in studying the centrosomal “pathway” in association with schizophrenia. Epistatic interactions on DISC1, PCM1, and related molecules may also be of interest for future studies.

View all comments by Akira Sawa

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 20 August 2006
Posted 23 August 2006

Regarding the possibility that PCM1 may have ties to DISC1, it's of interest that when PCM1 function is inhibited there is reduced targeting of centrin, pericentrin and ninein to the centrosome (1). Miyoshi and colleagues (2) report that their data indicate that DISC1 localizes to the centrosome by binding to kendrin/pericentrinB. Might there be a failure of DISC1 to localize in the centrosome in PCM1 deficiency?

Do these families with PCM1-associated schizophrenia also have a history of scleroderma? It is also of interest that PCM1 is an autoantigen target in scleroderma (3), and there is a report of cerebral involvement of scleroderma presenting as schizophrenia-like psychosis (4).

Abelson Helper Integration Site 1 (AHI1) gene is a candidate gene for schizophrenia and mutations in AHI1 underlie the autosomal recessive Joubert Syndrome in which cerebellar vermis hypoplasia is reported.(5) Increased cerebellar vermis white-matter volume has recently been reported in males with schizophrenia.(6)

It's interesting that mutations in the centrosomal protein nephrocystin-6 may also cause Joubert syndrome and that it activates ATF4. (7) Morris and colleagues (8) find that DISC1 interacts with ATF4 - a schizophrenia locus on 22q13 and ATF5. Perhaps failure of DISC1 to localize to the centrosome due to PCMI deficiency may also result in reduced activation of ATF4/5.

In view of the study by Al Sarraj and colleagues (9) finding that ATF4/5 stimulate asparagine synthetase activity might we suspect that reduced activation of ATF4 and ATF5 in schizophrenia may explain the decreased CSF asparagine levels reported (10) Perhaps asparagine synthetase might be a suitable drug target in schizophrenia. Of further relevance is the processed pseudogene for asparagine synthetase found upstream of GNAL -18p11, a region linked to bipolar disorder and schizophrenia. (11) Hirotsune and colleagues (12) report that an expressed pseudogene regulates messenger-RNA stability of its homologous coding gene.

Might we also suspect a role for DISC1 in oligodendrocyte dysfunction in schizophrenia? Reduced myelination is reported in neonatal rats deprived of asparagine?(13) It would seem relevant however that Mason and colleagues (14) find that ATF5 regulates proliferation and differentiation of oligodendrocytes, with loss of function resulting in accelerated oligodendrocyte differentiation

References:

1. Dammermann A, Merdes A. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. J Cell Biol. 2002 Oct 28;159(2):255-66. Epub 2002 Oct 28. Abstract

2. Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, Ogawa N. DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Commun. 2004 May 14;317(4):1195-9. Abstract

3. Bao L, Zimmer WE, Balczon R. Autoepitope mapping of the centrosome autoantigen PCM-1 using scleroderma sera with anticentrosome autoantibodies. Autoimmunity. 1995;22(4):219-28. Abstract

4. Muller N, Gizycki-Nienhaus B, Botschev C, Meurer M. Cerebral involvement of scleroderma presenting as schizophrenia-like psychosis. Schizophr Res. 1993 Aug;10(2):179-81. Abstract (5) Eur J Hum Genet. 2006 Jun 14; [Epub ahead of print] AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O, Mujaheed M, Segman RH, Maier W, Macciardi F, Beckmann JS, Lancet D, Lerer B. (6) J Psychiatr Res. 2006 Apr 18; [Epub ahead of print] Increased cerebellar vermis white-matter volume in men with schizophrenia. Lee KH, Farrow TF, Parks RW, Newton LD, Mir NU, Egleston PN, Brown WH, Wilkinson ID, Woodruff PW (7) Nat Genet. 2006 Jun;38(6):674-81. Epub 2006 May 7. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA,Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. (8) Hum Mol Genet. 2003 Jul 1;12(13):1591-608. Links DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Morris JA, Kandpal G, Ma L, Austin CP. (9) Biol Chem. 2005 Sep;386(9):873-9. Links Regulation of asparagine synthetase gene transcription by the basic region leucine zipper transcription factors ATF5 and CHOP. Al Sarraj J, Vinson C, Thiel G. (10) Nippon Rinsho. 1992 Jul;50(7):1643-9. Links [Amino acid metabolism in endogenous psychoses: significance of amino acids as neurotransmitter, precursor of monoamines and allosteric regulator of neuro-receptors] Doi N. (11) Mol Psychiatry. 2000 Sep;5(5):495-501. Links Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Vuoristo JT, Berrettini WH, Overhauser J, Prockop DJ, Ferraro TN, Ala-Kokko L. (12) Nature. 2003 May 1;423(6935):26-8. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A. (13) Dev Neurosci. 1982;5(4):332-44. Brain development in neonatal rats nursing asparagine-deprived dams. Newburg DS, Fillios LC. (14) Mol Cell Neurosci. 2005 Jul;29(3):372-80. ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, reene LA, Goldman JE.

View all comments by Mary Reid

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 10 September 2006
Posted 12 September 2006

Den Hollander and colleagues (1) report that mutations in CEP290-nephrocystin-6 are a frequent cause of Leber's Congenital Amaurosis (LCA). Autistic signs are reported in both Joubert syndrome and LCA (2,3). Perhaps asparagine may be useful for those with LCA and dysmyelination.

References:

1. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP. Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis. Am J Hum Genet. 2006 Sep;79(3):556-61. Epub 2006 Jul 11. Abstract

2. Curless RG, Flynn JT, Olsen KR, Post MJ. Leber congenital amaurosis in siblings with diffuse dysmyelination. Pediatr Neurol. 1991 May-Jun;7(3):223-5. Abstract

3. Rogers SJ, Newhart-Larson S. Characteristics of infantile autism in five children with Leber's congenital amaurosis. Dev Med Child Neurol. 1989 Oct;31(5):598-608. Abstract

View all comments by Mary Reid

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 25 September 2006
Posted 28 September 2006

The asparagine synthetase gene has been mapped to 7q21.3 (1). Childhood-onset schizophrenia/autistic disorder has been described in a child with a translocation breakpoint at 7q21. Of further interest is that alcohol/drug abuse, severe impulsivity, paranoid personality, and language delay have been reported in other family members carrying this translocation.

Maybe the increased risk of schizophrenia following famine may be explained by the fact that starvation induces expression of ATF4 and asparagine synthetase. Is there an increased risk of mutation in these genes as a long-term response to famine?

References:

1. Heng HH, Shi XM, Scherer SW, Andrulis IL, Tsui LC. Refined localization of the asparagine synthetase gene (ASNS) to chromosome 7, region q21.3, and characterization of the somatic cell hybrid line 4AF/106/KO15. Cytogenet Cell Genet. 1994;66(2):135-8. Abstract

2. Yan WL, Guan XY, Green ED, Nicolson R, Yap TK, Zhang J, Jacobsen LK, Krasnewich DM, Kumra S, Lenane MC, Gochman P, Damschroder-Williams PJ, Esterling LE, Long RT, Martin BM, Sidransky E, Rapoport JL, Ginns EI. Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21. Am J Med Genet. 2000 Dec 4;96(6):749-53. Abstract

View all comments by Mary Reid

Related News: Neuregulin, ErbB4 Drive Developmental Cell Fates

Comment by:  Cynthia Shannon Weickert, SRF AdvisorVictor Chong
Submitted 18 December 2006
Posted 18 December 2006

The study by Sardi et al. is truly remarkable. Their report of a novel ErbB4 cleavage-dependent mechanism regulating neuronal/astrocytic differentiation is groundbreaking, but their approach to unraveling and confirming this mechanism is more impressive. From their use of a yeast two-hybrid system in finding novel ErbB4 intracellular domain (E4ICD)-interacting factors to their meticulous experimental dissection of hypotheses and observations, the Corfas group has raised the bar in the investigation of mechanisms by which ErbB4 regulates neural precursor fates. In addition, the authors have shown that changes in E4ICD intracellular signaling pathways may produce cellular consequences distinct from those resulting from alterations in the activity of membrane-bound full-length ErbB4. More specifically, Sardi et al. illustrate that ErbB4 cleavage can regulate very early cell fates in the nervous system, while intact ErbB4 has mainly been examined in terms of its action at mature cortical synapses where its activation can dampen NMDA receptor function.

Recognition must also be given to Pat McCaffrey and Hakon Heimer, who provided an excellent summary of the article and highlighted the significance of the paper to schizophrenia. In the manuscript, disruptions in E4ICD signaling are discussed in terms of their relevance to Alzheimer disease. Since aberrant neuregulin-1-ErbB4 signaling has been implicated in schizophrenia, one could hypothesize that alterations in E4ICD-associated interactions and/or in the nuclear translocation of E4ICD complexes may contribute to schizophrenia pathology as well. Hence, it will be important to test whether either or both of these ErbB4-signaling streams are in fact altered not only in Alzheimer disease, but also in schizophrenia.

The difficulty in linking ErbB4 to neuropathological mechanisms underlying schizophrenia may be due in part to the limited information that exists on early developmental processes of this illness. In their paper, Sardi et al. suggest disruptions in ErbB4-dependent mechanisms may lead to premature astrogenesis that could contribute to Alzheimer disease-associated gliosis. However, in thinking about the relevance of altered E4ICD signaling in schizophrenia, elevated glial formation has not been observed in the schizophrenic brain. In fact, expression of the glial marker, GFAP, has been shown to be reduced in postmortem brains of subjects with this disorder (Johnston-Wilson et al., 2000; Webster et al., 2005). On the other hand, recent investigations suggest elevated prefrontal cortical feed-forward neuregulin-1-ErbB4 signaling in schizophrenia (Hahn et al., 2006), and this increase could lead to GFAP reductions possibly through the mechanism proposed by Sardi et al. if this elevated signaling translated to greater E4ICD cleavage. However, whether the findings of Sardi et al. in neural precursor cells extend to cells of the adult human brain remains to be explored. Nevertheless, the Corfas group has opened new avenues of research in the field of schizophrenia and has provided a framework for future studies on the role ErbB4 signaling in this disease.

References:

Johnston-Wilson N.L., Sims C.D., Hofmann J.-P., Anderson L., Shore A.D., Torrey E.F. and Yolken R.H. (2000) Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. Mol. Psychiatry. 5: 142-149. Abstract

Webster M.J., O'Grady J., Kleinman J.E. and Weickert C.S. (2005) Glial fibrillary acidic protein mRNA levels in the cingulate cortex of individuals with depression, bipolar disorder and schizophrenia. Neuroscience. 133: 453-461. Abstract

Hahn C.G., Wang H.Y., Cho D.S., Talbot K., Gur R.E., Berrettini W.H., Bakshi K., Kamins J., Borgmann-Winter K.E., Siegel S.J., Gallop R.J., Arnold S.E. (2006) Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12: 824-828. Abstract

View all comments by Cynthia Shannon Weickert
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Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

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 when ErbB signaling is abolished in oligodendrocytes, myelin structure appears normal, but the myelin sheath is significantly thinner. This is in line with some of the ultrastructural findings of Uranova’s group and in rodent studies looking at MAG-deficient mice (both reviewed in Davis et al., 2003)—another downregulated myelin-related gene found in brains of schizophrenia patients.

Reductions in oligodendrocyte number on the order of 20 percent have been demonstrated in the brains of schizophrenia patients (Hof et al., 2002). Although this finding does not precisely parallel the findings in this investigation, the authors’ adroitly point out that this may be because the abnormalities they induced were during early oligodendrocyte and myelin expression, while it is possible that the abnormalities seen in the brains of schizophrenia patients occur relatively later in development, more likely during the second large wave of cortical myelination at the end of the second decade of life. The authors also point out that “defects in ErbB signaling in different cell types may contribute to different aspects of psychiatric symptoms.” This might also be the case in schizophrenia, giving rise to the myriad presentations of the disease, as might the fact that expression of both NRG1 and ErbB4 are susceptible to environmental insult.

Other important similarities between the authors’ findings and schizophrenia include that, even in light of these myelin abnormalities, gross brain volumes, as well as several other measures, remained normal. This buttresses the idea that in schizophrenia, myelin abnormalities might be at the root of the often unimpressive brain changes noted in schizophrenia on gross structural imaging. And finally, although speculative, the authors do note an intriguing set of behavioral abnormalities, some of which could mimic the social isolation and poor relatedness of schizophrenia, which is particularly remarkable given the increased susceptibility to amphetamines and the trends seen in DAT, D1, and D2 expression in this investigation.

Corfas’s findings are indeed exciting, and we commend his team on an eloquently designed and implemented investigation.

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

Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

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 research.

The remarkable finding is that they observed alterations in dopamine-mediated neuronal networks and associated behaviors by disturbing NRG1/ErbB4 selectively in cells of oligodendrocyte lineage. Three important paradigms for schizophrenia (white matter pathology, dopamine, and a susceptibility gene) converge in this paper, and in this sense, I find it very exciting.

View all comments by Akira Sawa

Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

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.

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Related News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

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

Related News: Neuregulin and ErbB4: Synaptic Jacks of All Trades

Comment by:  Michael CahillPeter Penzes
Submitted 29 April 2011
Posted 29 April 2011
  I recommend the Primary Papers

The recent study by Pitcher et al. provides a novel mechanism linking NRG1/ErbB4 activity to the suppression of NMDAR activity in a manner requiring Src kinase inhibition. The study uses biochemical manipulation of Src activation, as well as studies on cells lacking Src, to examine the role for Src kinase on the effects of NRG1 on NMDAR responses in pyramidal neurons. Overall, the study provides convincing evidence indicating that Src inhibition by NRG1 is an important contributor to the effects of NRG1 on NMDAR pyramidal neuronal hypofunction. The effect of NRG1 and ErbB4 on Src family kinase activation remains complex. Previous studies have found that NRG1 can activate Src, and that inhibition of Src family kinases can block some of the effects of NRG1 on cells, including cellular migration and proliferation (Eckert et al., 2009; Grossmann et al., 2009). Moreover, ErbB4 activity is able to activate fyn when overexpressed in heterologous cells, and NRG1 treatment activates fyn in cells expressing endogenous ErbB4 (Bjarnadottir et al., 2007). Recent findings have similarly found that ErbB4 can activate Src kinases in heterologous cells and indicate that Src family kinase activation, particularly that of fyn, has a role in regulating the effects of NRG1 on interneuron morphology through RhoGEF activity (Cahill et al., 2011).

The findings of Picher et al. indicating that NRG1 can suppress Src kinase are not incompatible with these previously discussed studies, however. Indeed, studies have found that Src kinases can be both activated and inhibited by NRG1 treatment in a cyclic manner (Eckert et al., 2009), suggesting that the duration of NRG1 activity is an important consideration. The effects of NRG1 on pyramidal neuronal structure and/or function also seem to differ depending on the length of NRG1 treatment, as studies have found that chronic NRG1 or ErbB4 activity can promote synaptic structure and/or function (e.g., Barros et al., 2010; Li et al., 2007), whereas short-term NRG1 treatment is detrimental to pyramidal neuronal function (e.g., Wen et al., 2010), indicative of the importance of treatment duration to the functional consequences on neurons. The location of the examined effects is also an important consideration, as biochemical and morphological effects in pyramidal neurons and interneurons might differ following NRG1 treatment, potentially due to differences in ErbB4 expression profiles in these cells (Vullhorst et al., 2009). Given the links of NRG1/ErbB4 to schizophrenia, understanding how short-term and long-term activity of these molecules regulates both interneuron and pyramidal neuron function is of special importance, and merits further studies.

References:

Eckert JM, Byer SJ, Clodfelder-Miller BJ, Carroll SL. Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells. Glia . 2009 Nov 1 ; 57(14):1501-20. Abstract

Grossmann KS, Wende H, Paul FE, Cheret C, Garratt AN, Zurborg S, Feinberg K, Besser D, Schulz H, Peles E, Selbach M, Birchmeier W, Birchmeier C. The tyrosine phosphatase Shp2 (PTPN11) directs Neuregulin-1/ErbB signaling throughout Schwann cell development. Proc Natl Acad Sci U S A . 2009 Sep 29 ; 106(39):16704-9. 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

Cahill ME, Jones KA, Rafalovich I, Xie Z, Barros CS, Müller U, Penzes P. Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition. Mol Psychiatry . 2011 Apr 12. Abstract

Eckert JM, Byer SJ, Clodfelder-Miller BJ, Carroll SL. Neuregulin-1 beta and neuregulin-1 alpha differentially affect the migration and invasion of malignant peripheral nerve sheath tumor cells. Glia . 2009 Nov 1 ; 57(14):1501-20. Abstract

Barros CS, Calabrese B, Chamero P, Roberts AJ, Korzus E, Lloyd K, Stowers L, Mayford M, Halpain S, Müller U. Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc Natl Acad Sci U S A . 2009 Mar 17 ; 106(11):4507-12. 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

Wen L, Lu YS, Zhu XH, Li XM, Woo RS, Chen YJ, Yin DM, Lai C, Terry AV, Vazdarjanova A, Xiong WC, Mei L. Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons. Proc Natl Acad Sci U S A . 2010 Jan 19 ; 107(3):1211-6. Abstract

Vullhorst D, Neddens J, Karavanova I, Tricoire L, Petralia RS, McBain CJ, Buonanno A. Selective expression of ErbB4 in interneurons, but not pyramidal cells, of the rodent hippocampus. J Neurosci . 2009 Sep 30 ; 29(39):12255-64. Abstract

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