New scaffold supporting our molecular understanding of psychiatric disorders

Researchers establish a causative link between mutations in a single gene and the pathology of psychiatric illnesses

New work in mice indicates that defective function of the molecular ‘scaffold’ protein Disc1 results in behaviors resembling human schizophrenia and depression. Current treatments for these devastating diseases are palliative but not curative.

Prior work hints at a link between Disc1 and psychiatric illness. Some mood disorders in humans are ameliorated by drugs suppressing the function of PDE4B: a protein that binds to molecular scaffolds including Disc1 and metabolizes cAMP, a compound essential for transmission of cellular signals. From studies in humans, scientists are also aware of associations between Disc1 mutations and the incidence of psychiatric illnesses. However, whether these mutations altered Disc1 function, and thus whether Disc1 dysfunction actually contributed to brain pathology, was not determined.

An international group led by Yoichi Gondo, a scientist at RIKEN Genomic Sciences Center in Yokohama, used a mouse model to forge a causative link between alterations in Disc1 function and the pathology of psychiatric disorders. This work was published in a recent issue of Neuron (1).

The researchers used a chemical mutagen to scatter random infrequent mutations throughout the genome of laboratory mice, and extensive DNA sequencing to identify two mice that each contained a distinct mutation predicted to change the sequence of the PDE4B-binding region of Disc1.

Like brains of some patients with mood disorders, brains in mice expressing mutated versions of Disc1 were of small volume (Fig. 1 - Click on link below). However, although both mutated Disc1 proteins exhibited impaired binding to PDE4B, only one Disc1 mutant reduced PDE4B activity.

Mice expressing this Disc1 mutant exhibited behaviour characteristic of depression; these mice displayed reduced sociability and disinterest in pleasurable activities. In contrast, mice expressing the Disc1 mutant that left PDE4B function intact failed to process and respond to distracting stimuli; this behaviour is more reminiscent of humans with schizophrenia. PDE4B inhibitors ameliorated the behaviour only of mice expressing the latter mutant.

Whether mutations having similar consequences on Disc1 function arise naturally in humans is unknown. Nevertheless, these findings reveal a complex role of Disc1 in brain function, and suggest that psychiatric disorders caused by distinct lesions of Disc1 may require different treatments.

“Studies in mouse models should lead to precise molecular diagnostics for psychiatric illness and allow us to develop preventive and therapeutic medicines. The RIKEN mutant mouse library, from where these Disc1 mutant mice were obtained, provides mouse models for the study of many human diseases,” says Gondo.

1. Clapcote, S.J., Lipina, T.V., Millar, J.K., Mackie, S., Christie, S., Ogawa, F., Lerch, J.P., Trimble, K., Uchiyama, M., Sakuraba, Y., et al. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54, 387–402 (2007).

Published: 24 Aug 2007


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Websites: RIKEN RESEARCH Figure 1: Brains of both Disc1 mutants were smaller than those of unmutated mice. Left and right panels depict the average shrinkage patterns of several brains from schizophrenia-like and depression-like mutants with overall reduction of total brain volume to be 13% and 6%, respectively.