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Are Nodes of Ranvier Also Nodes for Psychosis?

13 September 2011. A new study points to the nodes of Ranvier—gaps in the axon's myelin sheath that boost the speed of electrical signals—as a gathering place for potential molecular culprits in schizophrenia. In particular, the report published online in Archives of General Psychiatry on September 5 highlights ankyrin-3, a protein involved in anchoring membrane proteins at these nodes. The gene for this molecule (ANK3) has strong support as a susceptibility factor for bipolar disorder (see SRF related news story; SRF related news story), as well as preliminary support in schizophrenia (Athanasiu et al., 2010).

Led by Vahram Haroutunian of Mt. Sinai School of Medicine in New York, the study built upon previous findings implicating white matter deficits in schizophrenia (Davis et al., 2003). First authors Panos Roussos and Pavel Katsel drew from postmortem, behavioral, and brain imaging data to build a case for abnormalities in several node of Ranvier genes, and downregulation of ANK3 in particular, in schizophrenia.

A survey of mRNA levels of genes involved in node of Ranvier construction and maintenance revealed several with abnormal expression patterns over 17 different brain regions in schizophrenia. Quantitative PCR analysis of eight of these genes confirmed this picture in another sample, finding mRNA reductions in ANK3, neurofascin (NFASC), neuronal cell adhesion molecule (NRCAM), and a sodium channel subunit (SCN8A)—one of the ion channels concentrated at the nodes—in the superior temporal gyrus (STG), but not the visual cortex. This suggests that the abnormalities were not brain-wide, but specific to regions previously implicated in schizophrenia.

Homing in on ANK3, the researchers found allele-associated differences in ANK3 expression. Specifically, homozygotes for the C allele at the bipolar disease-associated single nucleotide polymorphism (SNP) rs9804190 had a 27 percent decrease in ANK3 mRNA levels relative to T allele carriers within the schizophrenia group. The C allele was also associated with disease, with an odds ratio of 1.77 (permuted P = 0.03), in a schizophrenia sample of 208 cases.

The researchers also found cognitive repercussions of the C allele in healthy individuals in tests of working memory and executive function, which are impaired in schizophrenia. C allele homozygotes made more mistakes than T allele carriers in these tests, and showed abnormally increased activation in the prefrontal cortex during the working memory task.

With its hypothesis-based approach, this study paints ANK3 more clearly into the schizophrenia picture and adds to the case for shared genetic origins with bipolar disorder (see SRF related conference story; SRF related news story).—Michele Solis.

Reference:
Roussos P, Katsel P, Davis KL, Bitsios P, Giakoumaki SG, Jogia J, Rozsnyai K, Collier D, Frangou S, Siever LJ, Haroutunian V. Molecular and Genetic Evidence for Abnormalities in the Nodes of Ranvier in Schizophrenia. Arch Gen Psychiatry. 2011 Sep 5. Abstract

 
Comments on News and Primary Papers
Primary Papers: Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia.

Comment by:  Karoly Mirnics, SRF Advisor
Submitted 13 September 2011 Posted 13 September 2011

This is another good postmortem study from the Haroutunian laboratory. Although the studies are somewhat limited in scope and the conclusions are quite speculative (linking genetic, clinical, and cognitive disturbances to the dysfunction of the node of Ranvier), they are still a breeze of fresh air in schizophrenia research. They offer a new explanation of myelination deficits in schizophrenia, linking it to genetics and disturbed connectivity across the brain regions. We need such new hypotheses, new ideas. Is this one correct? It is certainly plausible, and supported by some data. However, if the past is a predictor of the future, we can be almost certain that the answer will be much more complicated than we think.

View all comments by Karoly Mirnics


Primary Papers: Molecular and genetic evidence for abnormalities in the nodes of Ranvier in schizophrenia.

Comment by:  Patrick Sullivan, SRF Advisor, Ann Collins
Submitted 21 September 2011 Posted 21 September 2011

Roussos and colleagues conducted a study that, in part, follows up findings from large-scale genetic association studies.

They hypothesized that there is a failure in saltatory conduction in schizophrenia and therefore potential dysfunction in the nodes of Ranvier (NOR) in schizophrenia. To evaluate this hypothesis, they performed microarray transcription analysis on multiple cortical regions in postmortem brain tissue from schizophrenia patients and controls. They selectively analyzed these transcriptome data for changes in genes which play a role in the NOR. They state that they identified dysregulation of genes known to be involved in development, organization, and maintenance of NOR across multiple brain regions. They were able to validate four of the genes using quantitative PCR, and to verify that these genes were not altered in brains of rats treated with haloperidol (i.e., less likely to be an effect of drug treatment).

Given the association of ANK3 in bipolar disorder, some evidence of association in schizophrenia, and the evidence of etiological overlap...  Read more


View all comments by Patrick Sullivan
View all comments by Ann Collins
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