Post by Former NIMH Director Thomas Insel: A Sampling of Summer Science
The summer is far from over, but already we can say that this has been an exceptional season for research on mental illness. Three recent discoveries are worth noting.
Gulsuner and colleagues just published a report on genes disrupted by de novo mutations in schizophrenia.1 These kinds of genetic mutations are called “de novo,” because they are not present in either parent’s blood cells but presumably arose via a mutation in either egg or sperm. These mutations are slightly more common in “sporadic” schizophrenia—those cases in which there is no family history of schizophrenia. De novo mutations are very common in the general population and probably most have no functional significance. Gulsuner and colleagues looked specifically at the subgroup of mutations predicted to be functional, based on the actual genetic change. These damaging mutations were found in 45 percent of people with schizophrenia, compared with 30 percent of their unaffected siblings. Such a modest increase may be statistically significant but it is not particularly informative.
This story became interesting when Gulsuner and colleagues looked at the specific genes involved. Using models of interactions, they found a surprising difference between the genes implicated in individuals with schizophrenia and those in their unaffected siblings. Relative to what was seen in controls, the 50 genes from the patients with schizophrenia were highly connected within a network critical for fetal organization of the prefrontal cortex. There was much less connectivity among these genes in other fetal brain areas and no evidence for a significant relationship to patterns of gene expression from the adult brain.
This finding builds on earlier reports that the genetics of neurodevelopmental disorders like schizophrenia may only make sense within the context of brain development, especially development in the second trimester of gestation.2,3 We already know from looking at the profound changes in gene expression between fetal and post-natal brain that the developing brain is virtually a different organ from that of adults (see http://www.brainspan.org/). But we still have much to learn about this “fourth dimension” of neuroscience—the critical times when the various players involved in building a brain do their precisely orchestrated jobs.
One of the ways questions about genes and development and disease will be answered is experimentally. Genetics will give us interesting leads, and modeling can suggest some likely pathways, but ultimately we need experiments that manipulate gene expression if we are to rule in or rule out a specific factor. The prospect of doing these kinds of experiments just got a lot better. In a paper just published, Konermann and colleagues have developed a technique for using light to alter gene sequences or epigenetic factors, the two major determinants of gene expression.4
Known by the acronym LITE (Light-Inducible Transcriptional Effectors), this new approach can be targeted to any group of brain cells and, with unprecedented precision, turn on or turn off specific genes in a behaving animal. The trick is that LITE uses light sensitive receptors to activate a target. This requires a fiber optic probe in the brain, so it is not ready for use in humans, but the impact of this new technique may well rival its predecessor, optogenetics, which uses light to manipulate circuit activity in the brain. The senior author on the LITE paper, Feng Zhang, was, in fact, the first author on the 2007 paper that initially described optogenetics.5
While neither of these stories gives us anything we can use in the clinic in the near term, if schizophrenia is the result of abnormal wiring during fetal development, as suggested by Gulsunger and co-workers, shouldn’t we be able to see the result in adulthood? There have been over 2,000 papers on schizophrenia and neuroimaging in the past decade. None has provided a biomarker and few have demonstrated large changes in connectivity between different areas of the cortex. A new report looks at connectivity between the cortex and thalamus, a deep brain area that has long been recognized as a kind of switchboard, critical for organizing and relaying information to all areas of the cortex.
Anticevic and co-workers compared connectivity between prefrontal cortex and thalamus first in a discovery approach with 90 patients diagnosed with schizophrenia versus 90 controls, then with a replication study including patients with a bipolar diagnosis.6 In people with schizophrenia there was over-connectivity from the thalamus to sensory-motor areas (closely correlated with symptoms) but under-connectivity to the prefrontal cortex. Similar but less marked findings were present in patients with a bipolar diagnosis, suggesting some shared neurobiology between these two syndromes characterized by psychosis.
While this connectivity finding is not yet a biomarker, this approach offers real promise for understanding how cortical function becomes dysregulated in people prone to psychosis. The connectome—the wiring diagram of our brains—is the result of the interplay between the genome, which provides the blueprint for brain development, and experience, which sculpts the developing brain. We may not be able to see or influence genomic variation, and the resulting effects on fetal wiring, but if we can detect the result, perhaps as changes in the connectome, we may have a way to detect risk for schizophrenia years before psychosis.
1 Gulsuner S et al. Spatial and Temporal Mapping of De novo Mutations in Schizophrenia to a Fetal Prefrontal Cortical Network. Cell, 2013 Aug. 1. http://dx.doi.org/10.1016/j.cell.2013.06.049. See also http://www.nimh.nih.gov/news/science-news/2013/stray-prenatal-gene-network-suspected-in-schizophrenia.shtml.
2 Nakata K et al. DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms. Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15873-8. doi: 10.1073/pnas.0903413106.
3 Colantuoni C et al. Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex. Brain Struct Funct. 2008 Sep;213(1-2):255-71. doi: 10.1007/s00429-008-0181-5.
4 Konermann S et al. Optical control of mammalian endogenous transcription and epigenetic states. Nature. 2013 Jul 23. doi: 10.1038/nature12466.
5 Zhang F et al. Multimodal fast optical interrogation of neural circuitry. Nature. 2007 Apr 5;446(7136):633-9.
6 Anticevic A et al. Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness. Cereb Cortex. 2013 Jul 3. doi:10.1093/cercor/bht165 [Epub ahead of print]