A paper just published online in nature neuroscience uses a new approach that searches for clusters of genes associated with mental illness-causing genetic variations—specifically, copy number variation (CNV). CNV resembles genomic imprinting in nullifying or amplifying the expression of specific genes. In genomic imprinting this comes about by way of silencing a gene from one parent rather than the other, and in CNV by means of duplicating or deleting the gene as a whole.  

Using the dosage changes associated with deletion or duplication of genes whose copy number varies in schizophrenia and autism, the researchers explored the available literature for phenotypes related to growth changes of dendrites. These are the branched projections spreading out from a nerve cell that conduct electrochemical signals received from other neural cells to the cell body, and, as such, clearly play a fundamental role in cognition (above). This analysis showed that whereas CNVs in autism primarily lead to an increase in growth of dendrites, CNVs in schizophrenia lead, on average, to the opposite effect (below) as earlier autopsy findings had suggested they might.

According to the imprinted brain theory, autism spectrum disorders (ASDs) such as Asperger’s syndrome and psychotic spectrum disorders (PSDs) such as schizophrenia are polar opposites, as I have described in numerous previous posts—notably the one on copy number variation (CNV).

The theory is unique in its simplicity and generality. According to The New York Times, "the new idea provides psychiatry with perhaps its grandest working theory since Freud, and one that is founded in work at the forefront of science." Basically it claims that genetic conflict between imprinted genes drives cognitive development in diametrically different directions: towards hyper-mentalism and PSD if maternal gene expression dominates, and towards mentalistic deficit (hypo-mentalism) and ASD if paternal genes do.  

Furthermore, because all fathers are male and all mothers are female, male versus female genetic conflicts are also involved which in their turn explain the observed trends relating to fetal testosterone and sex differences in brain laterality. Finally, because paternally active genes tend to be growth-enhancing and maternally active ones growth-restricting, the paternal trend goes with higher birth weight, more cancer, and larger brains in childhood and the maternal one with the contrary tendencies. 

The welcome result of the new research is that we now have another feature to add to the list in the diagram above:* more dendrites on the paternal side as our basic paradigm would predict, and less dendrites on the maternal side. It may be only a detail, but as I hope my readers will by now have realized, it is one that fits an already compelling picture—and indeed complements another recent finding that was the subject of an earlier post. Furthermore, this is a discovery that relates to an absolutely fundamental aspect of neurodevelopment. I have no doubt that many more will follow.

 *Modified and redrawn from Crespi, B. & Badcock, C. Psychosis and Autism as Diametrical Disorders of the Social Brain. Behavioral and Brain Sciences 31, 241–320 (2008).

(With thanks and acknowledgement to my colleague, Bernard Crespi, for bringing this to my attention.)

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The Imprinted Brain

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