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DISC1 Mouse Imaging Reveals Dopamine Dysfunction

28 January 2013. Mice carrying a truncated form of DISC1, a gene related to psychiatric illness, also show defects in the dopamine system akin to those found in schizophrenia. The study, led by Akira Sawa of Johns Hopkins University in Baltimore, Maryland, and published online on January 11 in Human Molecular Genetics, is the first to apply positron emission tomography (PET) to an animal model for psychiatric disorders.

While brain imaging of humans with psychiatric illness has revealed imbalances in neurotransmitter signaling, these findings do not easily translate to animal model development because most brain scanners do not pack the punch needed to get high-resolution pictures of a rodent’s smaller brain. As the availability of more powerful magnets and high-resolution techniques grows, however, small animal imaging is becoming a reality and could further validate animal models. In the new study, Sawa’s group used a 9.4 Tesla magnet to image the brains of the dominant-negative DISC1 mice developed in his lab, inspired by the DISC1-splitting chromosomal translocation found in a Scottish family enriched for mental illness. These mice express a truncated form of DISC1 in their cortices, and display schizophrenia-related brain pathology and behavior (see SRF related news story).

The new study reports signs of a dysregulated dopamine system in these mice. Using a D2 receptor-selective radioligand, the researchers found a small but significant increase in D2 receptors in the striatum compared to wild-type mice, and this surplus was further supported by autoradiographic counts of the receptors and PCR-measured transcript levels. This is consistent with the small but significant increase in D2 receptors found in the striata in unmedicated patients with schizophrenia (Howes et al., 2012; see also SRF Hypotheses). Using microdialysis, the researchers also found increased dopamine release in the striatum in response to methamphetamine, similar to the increase found in humans with schizophrenia.

Though it is unclear exactly how a change to DISC1 in the cortex could trickle down to modify dopamine signals in the striatum, the findings support a relationship between this animal model and psychotic illnesses like schizophrenia or some forms of depression (see SRF related news story).—Michele Solis.

Jaaro-Peled H, Niwa M, Foss CA, Murai R, Pou S, Kamiya A, Mateo Y, O'Donnell P, Cascella NG, Nabeshima T, Guilarte TR, Pomper M, Sawa A. Subcortical dopaminergic deficits in a DISC1 mutant model: a study in direct reference to human molecular brain imaging. Hum Mol Genet. 2013 Jan 11. Abstract

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