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2 March 2010. If schizophrenia has its roots in early brain development, why does the disease most often appear in adolescence or early adulthood? A new mouse model of DISC1 knockdown may provide some clues to that mystery. In a paper published in the February 25 issue of Neuron, Akira Sawa of Johns Hopkins University in Baltimore, Maryland, Toshitaka Nabeshima of Meijo University in Nagoya, Japan, and colleagues present data showing that a transient prenatal loss of DISC1 protein in the developing cortex in mice is sufficient to cause problems in dopaminergic circuits later on. After puberty, the animals showed both neurotransmitter changes (low dopamine levels) and behavioral changes that have been proposed to model aspects of schizophrenia in animals. The results tie an early developmental snafu to changes in later brain maturation, and provide a method for creating animal models to test the impact of genetic risk factors on development and disease.
The DISC1 (disrupted in schizophrenia-1) gene was first identified in a Scottish family where its truncation by a chromosomal translocation causes schizophrenia and other serious mental disorders. Since then, DISC1 has been found to play important roles in both neuronal development and in brain function in the adult brain (see SRF related news story; SRF related news story; and SfN 2009 meeting coverage). However, just how its loss precipitates schizophrenia is not clear. In previous work from the Sawa group, Atsushi Kamiya showed that a prenatal knockdown of DISC1 in vivo by in utero electroporation of short hairpin RNA into cortical progenitor cells in rats led to abnormal neuronal migration, impaired orientation, and loss of proper dendritic trees (see SRF related news story).
In the new work, Kamiya and co-first author Minae Niwa extend those findings by looking at the long-term structural and behavioral effects of transient loss of DISC1, this time in mice. To do that, they used in vivo electroporation of short hairpin RNAs to target cortical progenitor cells lining the brain ventricles, which mature mainly into pyramidal neurons of the prefrontal cortex. The result was a temporary loss of DISC1 protein in the cells, which lasted until shortly after birth and caused defects in progenitor proliferation, neuronal migration, and changes in arborization, particularly in layer II/III of the cortex. These changes, apparent at two weeks after birth, are consistent with the earlier results of Kamiya and others (Mao et al., 2009). The neurons also showed changes in function, as measured by membrane resistance and capacitance.
The researchers went on to ask if these early changes translated into problems later on. They analyzed four- and eight-week-old mice and found no gross changes in body weight or brain structure, or signs of gliosis in the cortex. However, they did detect a decrease, by nearly 50 percent, of dopamine content in the cortex in the eight-week-old mice, contrary to the usual increase that occurs with maturation. The loss was associated with a decrease in tyrosine hydroxylase positive (dopaminergic) projections in the cortex. Other changes included a reduction in parvalbumin staining in cortical GABAergic interneurons, and electrophysiological alterations in pyramidal neurons. Similar changes have been noted in brain tissue from people with schizophrenia, including reports of decreased arborization and smaller size of interneurons in layers II/III of the cortex, alterations in a subset of parvalbumin-positive interneurons, and reduction in tyrosine hydroxylase staining.
“Taken together, these results suggest that neonatal pyramidal neuron deficits elicited by pre-/perinatal knockdown of DISC1 lead to overall disturbances in circuitry involving dopamine neurons, pyramidal neurons, and interneurons, manifested only after puberty,” the authors write. Of note, the mice did not show changes in dopamine in other brain regions, nor were other neurotransmitters changed in the cortex. No changes were seen in levels of the dopamine receptors D1 or D2.
The mice also displayed behavioral changes proposed to model aspects of schizophrenia. Eight-week-old animals, but not four-week-olds, showed decreased prepulse inhibition, thought to reflect a defect in sensory gating seen in several mental illnesses. Treatment of animals with clozapine normalized dopamine levels and erased the PPI deficit. Other proposed schizophrenia-related phenotypes reported included impaired memory in the novel object recognition test (also improved by clozapine) and hypersensitivity to methamphetamine.
“The present study indicates the sequential link among pre-/perinatal disturbances in a specific genetics susceptibility factor (DISC1), the associated dendritic abnormalities in the neonatal stage, and, in turn, selective phenotypes in adolescence and adulthood,” the authors conclude. The results raise a host of mechanistic questions, from the role of DISC1, to how dendritic abnormalities in layer II/III neurons might lead to decreased dopamine projections, to what might be the trigger that precipitates post-puberty pathophysiology.
Sawa, Nabeshima, and colleagues suggest that the technique of in utero gene transfer opens up the chance to build new animal models by manipulating multiple genes during development and watching how they influence adult behavior. Co-transfection techniques allow for the possibility of testing synergistic or epistatic effects of genes, and the electroporation can be modified to target other neuronal populations. This could be especially useful for adult mental disorders, they write, “including schizophrenia, in which multiple risk factors play etiological roles during neurodevelopment.”
In an accompanying preview, Barbara Thompson and Pat Levitt of the Keck School of Medicine, University of Southern California in Los Angeles, write that the study shows how an early and transient insult can lead to a systemic breakdown and the emergence of a disease state “even in the context of what appears on the surface to be minor ‘cracks’ in brain architecture and molecular status.” The study also raises the “frightening thought that one may never be able to identify signature patterns of psychiatric disease risk, because such early changes may be undetected as a result of the restricted and highly transient nature of the spatial and temporal insults,” they write.—Pat McCaffrey.
References:
Niwa M, Kamiya A, Murai R, Kubo K, Gruber AJ, Tomita K, Lu L, Tomisato S, Jaaro-Peled H, Seshadri S, Hiyama H, Huang B, Kohda K, Noda Y, O’Donnell P, Nakajima K, Sawa A, Nabeshima T. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron. 2010 February 25;65:480-489. Abstract
Thompson BL, Levitt P. Now you see it, now you don’t—Closing in on allostasis and developmental basis of psychiatric disorders. Neuron. 2010 February 25;65:437-439. Abstract
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