21 January 2010. Disrupted in schizophrenia 1 (DISC1) is one of the most promising schizophrenia gene candidates, but exactly how it might increase susceptibility to the disease is unclear. One theory is that mutations suppress the gene, causing early developmental problems that predispose to the later emergence of symptoms. An alternative hypothesis is that those developmental problems are caused not by loss of the protein but by DISC1 protein fragments that block the function of the normal protein. New research supports the latter interpretation and also emphasizes that the timing of DISC1 gene activity could be a crucial factor in the disease. In the January 5 Molecular Psychiatry online, researchers led by Mikhail Pletnikov at Johns Hopkins University School of Medicine, Baltimore, Maryland, report that overproduction of DISC1 at various times during mouse brain development can precipitate different behaviors that may model vulnerability to schizophrenia or depression.
DISC1 was first discovered in an extended Scottish family. A mutation, specifically the replacement of a section of chromosome 1 with DNA from chromosome 11, interrupts the gene and truncates the protein product. The smaller DISC1 is rapidly degraded in some cells, but it is not clear if it is stable enough in neurons to have a physiological role. The new findings support the idea that truncated DISC1 fragments may act as dominant-negative suppressors of normal DISC1 activity in the brain.
To test the dominant-negative theory, Pletnikov and colleagues generated a mouse model in which overexpression of a truncated human DISC1 mutant (hDISC1) is regulated by an inducible promoter system that can be turned off. Previously, these researchers reported that keeping the promoter on throughout development can lead to schizophrenia-like behavioral symptoms (see SRF related news story). In this study they examined the effects of having the gene turned on or off at specific times during development. First author Yavuz Ayhan and colleagues looked at four different expression patterns: hDISC1 expressed prenatally, postnatally, both, and not at all. They found that morphological and behavioral abnormalities that ensued depended on when hDISC1 overexpression was initiated. The outcomes were also different in male and female animals.
Ayhan and colleagues report that the most robust effects were seen when hDISC1 expression occurred both pre- and postnatally. Under this scenario, three- to seven-month-old male mice were more aggressive than control animals and were more sensitive to NMDA glutamate receptor antagonists and amphetamines, which can induce psychosis-like behavior in humans and are often used in animals to model aspects of schizophrenia. Male mice also had reduced levels of dopamine in the brain. Female mice showed no aggressive characteristics but did have an increased propensity for depression. These behavioral changes were accompanied by gross anatomical changes in both male and female mice. Lateral ventricles, which are consistently enlarged, on average, in schizophrenia patients, were bigger in the animals, and there was reduced cortical volume. The number of parvalbumin-positive neurons was decreased in frontal, temporal, and parito-occipital cortices. Synaptic density in the dentate gyrus was increased.
Only some of these abnormalities were seen when hDISC1 expression was limited to pre- or postnatal periods alone. When expressed after birth, hDISC1 caused male mice to exhibit less non-aggressive social behavior but no increase in aggressive behavior. Female mice were also more susceptible to depression. Lateral ventricles were increased and cortical volume reduced as when hDISC1 was expressed pre- and postnatally, but the reduction in parvalbumin-positive interneurons was restricted to the frontal and parito-occipital cortices. There was a reduction in dopamine in the brains of both male and female mice. Expressed only before birth, hDISC1 had no effect on subsequent behavior, and there was no change in lateral ventricle or cortex volumes. Reductions in parvalbumin-positive neurons was restricted to the frontal cortex alone, and dopamine was reduced in only male mice. Interestingly, there was a reduction in overall brain volume in these mice that was not seen when hDISC1 was overexpressed during the other time periods, and there was an increase in synaptic density in the cortex that was specific to mice expressing hDISC1 prenatally as well.
“The primary conclusion of our study is that the effects of mutant hDISC1 are qualitatively and quantitatively different, depending on when during neurodevelopment the protein is expressed,” write the authors. How the work relates to schizophrenia or the other psychiatric disorders linked to the gene is not fully clear, but the authors note that the translocation in the human gene has been linked to diverse clinical manifestations which may relate to timing of expression. Previously, early postnatal, but not adult, expression of a C-terminal portion of DISC1 was shown to cause phenotypes that included depression, reduced sociability, and poor spatial working memory (see SRF related news story). Interestingly, in contrast to Pletnikov’s model, C-terminal DISC1 also caused reduced dendritic complexity in this earlier study.
Several other models have also been reported. In general, the models show similar behavioral and morphological abnormalities, though there are some differences. In Pletnikov’s model, as well as two single point mutation mouse models (see SRF related news story), and another model that expresses a truncated DISC1 (see Shen et al., 2008), the lateral ventricles are increased in size. In the latter model, parvalbumin-positive neurons are also sparse compared to control mice. The point mutation models also lead to depression-like symptoms and aberrant social behavior, and seem unique in causing deficiencies in prepulse inhibition, a phenomenon that is often compromised in patients with schizophrenia. All told, the varying models of DISC1 function support the idea that early neurodevelopmental problems can predispose people to schizophrenia and other major neuropsychiatric disorders, such as depression. These mouse models may prove useful in figuring out how to find treatments for later symptoms.—Tom Fagan.
Ayhan Y, Abazyan B, Nomura J, Kim R, Ladenheim B, Krasnova IN, Sawa A, Margolis RL, Cadet JL, Mori S, Vogel MW, Ross CA, Pletnikov MV. Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Mol Psychiatry. 2010 Jan 5. Abstract