July 16, 2013. Truncating both copies of the disrupted in schizophrenia 1 (DISC1) gene in mice impairs cognition and motivation, and leads to signs of oxidative stress in the brain, according to a study published July 8 in the Proceedings of the National Academy of Sciences. Led by Akira Sawa and Michela Gallagher, both at Johns Hopkins University in Baltimore, Maryland, the study delves into the effects of truncated copies of DISC1, which are proposed to interfere with normal DISC1 function. Mice homozygous for this putative dominant negative form (DN-DISC1) had problems adapting their behavior to changing conditions, were less likely to work for reward, and showed signs of oxidative stress in prefrontal cortex.
The results link DISC1 to the realms of motivation and behavioral flexibility, which are compromised in psychiatric disorders. Because DISC1 features as a player in neurodevelopment and synapse function (see SRF related news story), it may not be a surprise that it influences disparate domains of brain function. The same group, however, previously reported subtle phenotypes in mice heterozygous for DN-DISC1 (see SRF related news story), and so they set out to look at homozygotes. The DN-DISC1 model introduces a truncated form of the protein that mimics a product of the DISC1-disrupting chromosomal translocation found in a Scottish family beset by mental illness. Sawa and colleagues have proposed that this truncated DISC1 would bind normal DISC1 and prevent it from doing its job.
The study also suggests calming oxidative stress as a therapeutic approach for psychiatric diseases. Oxidative stress results when cells are overwhelmed by reactive oxygen molecules, and this condition can do some lasting damage in non-renewing neurons. Evidence for oxidative stress in schizophrenia comes from animal models (see SRF related news story) and from the decreased numbers of parvalbumin-containing interneurons found in schizophrenia. These fast-spiking, metabolically hungry neurons may be especially vulnerable to oxidative stress (see SRF related news story).
Fixated and unmotivated
First authors Alexander Johnson and Hanna Jaaro-Peled compared homozygous DN-DISC1 mice that resulted from breeding the heterozygous DN-DISC1 mice. Wild-type mice that were not littermates served as controls. As a first test of cognitive function, the researchers tested mice on reversal learning, which relies on the orbitofrontal cortex and measures how well the brain can change to a new set of rules. For example, the mice learned that poking their nose to the left would get them a sucrose reward, while poking it to the right would not. When the researchers switched the rules so that poking to the left gave no reward, but poking to the right did, control mice updated their behavior to the new rules, but DN-DISC1 mice initially did not.
Further testing suggested that this impairment stemmed from problems with connecting information about the value of a reward to behavior. For example, the researchers decreased the value of a food reward by letting the mice eat that food before the test—effectively ruining their appetite for that food. When they did this, the DN-DISC1 mice continued to press a lever associated with the food with gusto, as much as another lever that delivered a food they had not been fed ahead of time. In contrast, control mice scaled back their responses to the devalued food lever. This suggests a problem in getting the value of an outcome to shape behavior in DN-DISC1 mice.
Understanding how information about outcomes guides behavior also enters into the domain of motivation, and here the researchers also found differences in DN-DISC1 mice. When more effort was required to get a reward, this increased pleasure-related licking to that reward in control mice, but not in DN-DISC1 mice. This again suggests a disconnect between the value of something and its effect on behavior, which can be taken as a sign of reduced motivation. In another test, the researchers made it progressively harder for the mice to get their reward: Mice initially received sucrose after making 20 licks at an empty well, but the requirement gradually ratcheted up to 300 licks. Though the DN-DISC1 mice showed a normal preference for sucrose, they licked half the number of times controls did over the course of this test. Eventually, all DN-DISC1 mice (compared to half of the controls) quit licking altogether before the test was completed.
The researchers then examined the prefrontal cortex for signs of oxidative stress. They found increased 8-oxo-dG staining, which marks spots of oxidative damage in DNA, in the orbitofrontal cortex in DN-DISC1 mice relative to controls. Another sign came in the form of the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH): Under conditions of oxidative stress, GAPDH binds to a protein called Siah, and together they travel to the nucleus to spur a cascade of events. The researchers found a 10-fold increase in GAPDH-Siah binding in DN-DISC1 mice compared to controls. This increase occurred in prefrontal cortex, but not striatum, a brain area that interacts with prefrontal cortex. Although DN-DISC1 heterozygous mice have a reduced number of parvalbumin-containing neurons (see SRF related news story), the researchers did not report any pathology related to these neurons in DN-DISC1 homozygous mice.
The researchers mention they have developed inhibitors of the GAPDH cascade, but they do not test them in this study. If quelling oxidative stress normalizes cognition and motivation in these mice, this may pave the way for new therapeutics for psychiatric disorders. For now, it seems DISC1 has added a few more things to its bag of tricks, and future experiments will have to detail how DN-DISC1 expression leads to oxidative stress in prefrontal cortex.—Michele Solis.
Johnson AW, Jaaro-Peled H, Shahani N, Sedlak TW, Zoubovsky S, Burruss D, Emiliani F, Sawa A, Gallagher M. Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proc Natl Acad Sci U S A. 2013 Jul 9. Abstract