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Putting 2 and 2 Together—Chromosomal Deletions and Neurodevelopment in Schizophrenia Susceptibility

15 September 2009. Though genetic variation and neurodevelopmental problems are both thought to play a role in the etiology of schizophrenia, linking the two has not been easy. In the September 11 PNAS online, Anthony-Samuel LaMantia and colleagues from the University of North Carolina at Chapel Hill report that genetic deletions on the q11 section of chromosome 22 have a profound impact on the development of the mouse cerebral cortex. By extrapolation, the research suggests that in people with 22q11 deletions, also known as DiGeorge or velocardiofacial syndrome, schizophrenia is a result of early brain development gone awry. In particular, the research points to interference with parvalbumin-expressing interneurons, which have been linked to schizophrenia in numerous other studies. This finding may help scientists better understand schizophrenia in 22q11 deletion patients, and in general.

Chromosome 22q11 deletions are the strongest known genetic risk factor for schizophrenia, with about 25 percent of carriers succumbing to the disease (see Murphy et al., 1999 and Bassett et al., 2005). The deletions also increase susceptibility to autism spectrum disorders and general learning and behavioral disabilities. Which of the missing 22q11 genes are needed to avoid these conditions is unclear. The deleted region hosts genes for proteins involved in neurotransmission (see SRF related news story), for microRNAs that can exert control over many other genes, and for proteins linked to prepulse inhibition, a potential schizophrenia endophenotype, or biological marker (see SRF related news story). Brain imaging also shows that patients with 22q11 deletions have anatomical defects, including reduced cortical gray matter, indicative of neurodevelopmental problems.

To investigate the latter, LaMantia’s group has turned to the LgDel mouse, a model of 22q11 deletion syndrome. First author Daniel Meechan and colleagues used a combination of BrdU labeling, which identifies proliferating cells, and neural progenitor markers to see if neurogenesis and neural migration are altered in the mice. During development, new cells arising from sites of neurogenesis must migrate and integrate into their correct position for proper morphological development of the brain.

The researchers focused on basal and apical progenitors since they play primary roles in brain development. They found that the number of basal progenitors was significantly reduced in LgDel embryos compared to wild-type. In contrast, the numbers of apical progenitors appeared normal and their radial processes, which serve as a conduit for migrating neurons, were also unchanged. The findings indicate that developmental abnormalities in the LgDel mouse brain might predominantly arise from basal progenitor deficiencies.

Since basal progenitors give rise to projection neurons that fill in layers 2-4 of the cerebral cortex, the researchers looked to see if there were any morphological differences in this area of the brain in five-day-old LgDel pups. They found reduced frequency of neurons in the medial, but not lateral or dorsal cortices, and they attributed this to loss of layer 2-4 neurons, based on the distribution of Cux1, a layer 2-4 protein marker. Cux1-positive neurons were reduced by 20 percent in the medial cortex. The authors also found reduction in parvalbumin interneurons in the medial cortex of 21 day old mice, which may be directly related to the projection neuron loss, according to the authors.

“Our results suggest local changes in gray matter and neuropil, deduced from imaging and pathological assessment in 22q11DS patients, may reflect altered identity, abundance, and connections of projection neuron classes due to disrupted basal progenitor proliferation, and parallel changes in interneuron migration and placement during development,” write the authors. And they add that these findings support the neurodevelopment hypothesis of 22q11 deletion cognitive disorders.

Which of the chromosome 22q11 genes are needed to circumvent these developmental problems is not completely clear, but Meechan and colleagues did examine a short list. Two candidate genes, Tbx1 encoding a transcription factor, and the gene for proline dehydrogenase, do not seem to be involved since ablating one copy of Tbx1 and even two copies of Prodh had no effect on basal progenitors (though they might contribute to the syndrome in different ways see SRF related news story). The authors did find, however, diminished cortical expression in LgDel mice of six 22q11 genes linked to the cell cycle. Genetic variations in one of the genes, RANBP1, have been linked to schizophrenia in non 22q11 deletion patients (see Liu et al., 2002), making it a particularly interesting candidate.—Tom Fagan.

Meechan DW, Tucker ES, Maynard TM, Lamantia AS. Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome. Proc Natl Acad Sci U S A . 2009 Sep 22 ; 106(38):16434-45. Abstract

Comments on News and Primary Papers
Comment by:  Brian Morris
Submitted 5 October 2009
Posted 5 October 2009

The dramatically increased risk of schizophrenia associated with velocardiofacial/DiGeorge syndromes (VCFS/DGS) can potentially provide us with a unique insight into the causes of the disease. This study is interesting in that it provides further evidence that reduced levels of expression of the genes encoded in this short region of chromosome 22 are sufficient to cause neurodevelopmental impairments in cerebrocortical neurons. It is worth remembering, as noted above, and as emphasized by the authors, that VCFS/DGS are associated with increased risk of a number of mental health problems with a neurodevelopmental component, not just schizophrenia. In fact, the cortical abnormality reported in this paper that can be specifically associated with schizophrenia (altered parvalbumin neuron distribution) is really subtle. Nevertheless, the study suggests that reduced expression of these few genes on chromosome 22 may be sufficient to cause cortical parvalbumin neuron dysfunction. In turn, this provides some support for the theory that cortical GABA interneuron impairments are an early event in the etiology of schizophrenia, and not simply a consequence of the cortical dysfunction arising from other causes.

The number of genes in the VCFS/DGS deletion region is small, and studies using gene-specific knockouts can provide further insight into the mechanisms leading to altered cortical function in schizophrenia.

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