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Do Faulty Nogo Receptors Allow Axons to Run Amuck in Schizophrenia?

7 January 2009. It was reported several years ago that the gene for Nogo-66 receptor 1 (NGR, or RTN4R), located in the chromosome 22q11 region, may influence genetic predisposition to schizophrenia (Liu et al., 2002). Stephen Strittmatter and colleagues of Yale University in New Haven, Connecticut, find support for this association in a study published in the December 3 issue of the Journal of Neuroscience. NgR1 mediates myelin-associated inhibition of axon growth, and the researchers also report that rare variants of NgR1 found in people with schizophrenia failed to inhibit axonal growth in vitro.

Reduced myelination, oligodendroglial dysfunction, and the reduced expression of several myelination-related genes have been associated with schizophrenia (see SRF related news story and SRF news story). The brains of people with schizophrenia are reported to have abnormal myelination patterns, which may contribute to the disease (for review, see Karoutzou et al., 2008; Segal et al., 2007). The current report lies at the nexus of this line of research and another that seeks to discover why hemizygous deletion of the 22q11 locus confers an increased risk of schizophrenia (Baron, 2001).

Oligodendrocytes in normal brain regulate axonal growth via Nogo protein and its receptor, NgR1. The Nogo receptor is well established to regulate growth cone collapse by binding Nogo associated with myelin, thereby stopping axon growth. In normal development, this process could lead to the establishment of appropriate axonal pathways. In schizophrenia, faulty NgR1 signaling could conceivably cause axonal miswiring.

The Yale researchers, led by first author Stephane Budel, studied several ethnic populations each consisting of people with schizophrenia and an approximately equal number of controls without schizophrenia: 636 Caucasians, 296 African Americans, and 1,122 Chinese. They analyzed seven single nucleotide polymorphisms (SNPs) associated with NGR, and in Caucasians, they were able to identify a group of SNPs, or haplotype, that is significantly associated with schizophrenia. The scientists analyzed whether the results could have been accounted for by genetic variation between the control group and the group with schizophrenia, but no differences between the genetic backgrounds of the two groups were found. In the African American and Chinese groups they found no significant association between changes in the NGR1 locus and schizophrenia.

Strittmatter and his co-workers also examined how changes in NgR1 protein function might contribute to schizophrenia. A detailed examination of DNA from an NIMH collection of samples taken from people with schizophrenia predicted that amino acid substitutions at position R377 in the NgR1 protein were common. The researchers examined the function of two altered forms of NgR1 that had amino acid substitutions at position 377: substituting either glutamine (Q) or tryptophan (W) for arginine (R). They transfected chick retinal neurons, using a herpes virus, causing them to express the altered forms of NgR1. In wild-type chick retinal neurons, growth cone collapse normally occurs in response to Nogo protein, but in the R377Q-NgR1 and R377W-NgR1 cells, Nogo-66 exposure did not collapse growth cone. This effect was also seen with exposure of the cells to myelin-associated glycoprotein and with myelin. The R377Q-NgR1 cells were less likely to experience growth cone collapse than wild-type cells and R377W-NgR1 cells were the least likely to experience growth cone collapse.

The scientists were also interested in amino acid substitutions R119W and R196H in the NgR1 protein, based on a report from a different research group (Sinbaldi et al., 2004). When these amino acid changes were expressed in NgR1 in chick retinal neurons, neither cells with R119W nor R196H mediated growth cone collapse in response to Nogo-66, myelin associated glycoprotein, or myelin.

Strittmatter and co-workers also tested whether changes in functional NgR1 affect the performance of mice in tests of cognitive function and affect, since both can be altered in people with schizophrenia. They observed impairment of working memory in NGR knockout mice (NGR1-/-), relative to wild-type, using a delayed alternation task. However, they did not see deficits in spatial memory, as NGR knockouts performed similarly to wild-type animals in a water radial arm maze. They also saw no differences in passive-avoidance learning between the two sets of mice by using tests in which mice learned to avoid an electric shock. A light-dark exploration test revealed no differences in anxiety-like behavior between wild-type and NGR knockout mice. Based on these experiments, the cognitive and emotional effects of changing Nogo-66 signaling by eliminating its receptor seem to be restricted to causing problems with working memory.

Based on this report, it seems that in at least some cases of schizophrenia, faulty myelin may be to blame for mixing up neuronal signaling by misdirecting axon growth. The authors conclude that “…one mechanism for increased schizophrenic risk is a failure to restrict anatomical plasticity in the brain.” Myelin-mediated inhibition of axonal sprouting may be a final stage of neuronal development that occurs during adolescence. This fits in with the idea that schizophrenia generally develops around early adulthood. Failure of the NgR1 pathway to inhibit axonal growth in late adolescence could cause abnormal brain connectivity and schizophrenia symptoms. It is interesting that the researchers found these effects in a group of Caucasians specifically. It is conceivable that similar disruptions in axonal remodeling may occur in other ethnic groups based on changes in NgR1 signaling, perhaps via slightly different gene and protein alterations. Stephane Budel told Schizophrenia Research Forum that, “We reached statistical significance only in Caucasians, but cannot rule out that NgR may participate in schizophrenia in other ethnicities.”

Interestingly, a report by Hsu and colleagues in a group led by Joseph Gogos came to quite different conclusions regarding the importance of NgR1 in schizophrenia (Hsu et al., 2007). These researchers found only a weak association between schizophrenia and NgR1 polymorphisms, by using a similar SNP analysis and evaluating samples taken from a family of Afrikaner origin. However, when they examined the behavior of NGR1-/- mice, they failed to see differences in working memory between the Nogo receptor-deficient mice and wild-type mice, as measured using a delayed alternation task. They also failed to see an effect in other schizophrenia-related behavioral tasks, although NGR1-/- mice did appear to have less motor activity than wild-type animals, as measured by an open-field test. The investigators in this study concluded that although NgR1 may not play a major role in conferring schizophrenia susceptibility, it may be one genetic influence that affects risk for schizophrenia in some patients.—Alisa Woods.

Reference:
Budel S, Padukkavidana T, Liu BP, Feng Z, Hu F, Johnson S, Lauren J, Park JH, McGee AW, Liao J, Stillman A, Kim JE, Yang BZ, Sodi S, Gelernter J, Zhao H, Hisama F, Arnsten AF, Strittmatter SM. Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth. J Neurosci. 2008 Dec 3;28(49):13161-72. Abstract

 
Comments on News and Primary Papers
Comment by:  Takeshi SakuraiJoseph D. BuxbaumPatrick R. Hof
Submitted 9 January 2009 Posted 9 January 2009

Several lines of evidence indicate that oligodendrocytes and myelin are disturbed in schizophrenia (Davis et al., 2003; Segal et al., 2007). However, the relationship of these alterations to the pathogenesis of schizophrenia is still unclear. A recent paper by Budel et al. proposes one possible link between oligodendrocyte and myelin pathology and schizophrenia pathogenesis. The gene for Nogo-66 receptor 1 (RTN4R) is located within the 22q11.2 locus where a hemizygous microdeletion (1.5 Mb) occurs at a frequency of one in 5,000. Twenty to 30 percent of individuals with the deletion develop schizophrenia. Several candidate genes for the schizophrenia phenotype within this locus have been characterized for genetic association, and common variants of the Nogo-66 receptor 1 gene have shown association in one study (Liu et al., 2002), but replication studies have not confirmed the findings using different cohorts (  Read more


View all comments by Takeshi Sakurai
View all comments by Joseph D. Buxbaum
View all comments by Patrick R. Hof

Comment by:  Ruby Hsu
Submitted 9 February 2009 Posted 10 February 2009

Individuals with hemizygous microdeletions at the 22q11.2 locus display a range of cognitive and behavioral deficits, and compared to the general population these individuals have a greatly increased risk of developing schizophrenia (Karayiorgou et al., 1995). A number of candidate schizophrenia susceptibility genes have been identified within the 22q11.2 region (Mukai et al., 2004; Paterlini et al., 2005; Paylor et al., 2006; Stark et al., 2008). In our paper (Hsu et al., 2007), we evaluated RTN4R (NgR1), one of the genes in the 22q11.2 region, as a schizophrenia susceptibility gene using a variety of approaches including human association analyses as well as mouse behavioral and anatomical assays. We evaluated common RTN4R variants in a large Afrikaner family sample and found RTN4R polymorphisms which...  Read more


View all comments by Ruby Hsu

Comment by:  Georgia Karoutzou
Submitted 26 February 2009 Posted 26 February 2009

This is a thorough and generally well-written manuscript that provides further evidence to the hypothesis that schizophrenia may be viewed as a disconnectivity syndrome (Frith, 1996; Davis et al., 2003) due to disturbances in myelination.

Even though the authors examined a large sample consisting of 3 different populations (Caucasians, African-Americans and Chinese Han trio sample), they do not provide details regarding the age-ratio of these populations, nor do they report the treatment of these patients. Hence, there is a growing body of evidence of age-related changes in the human brain (Allen et al., 2005).We consider that the authors of this study fail to investigate of how the effects of age are expressed. It can not be ruled out whether there is any effect of the medication in the observed results. Even though medication is not implicated in the observed alterations in gene expression in schizophrenia in several studies (  Read more


View all comments by Georgia Karoutzou
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