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Schizophrenia’s “Rosetta Stone” Gene
Industry Insight

Schizophrenia’s “Rosetta Stone” Gene

Schizophrenia’s “Rosetta Stone” Gene
Industry Insight

Schizophrenia’s “Rosetta Stone” Gene

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Schizophrenia is a chronic, severe, and disabling brain disease which affects approximately 1 percent of the population and at present is challenging to diagnose accurately. Currently, the only treatment for the disease relies on symptom based diagnosis followed by administering drugs to ease these symptoms.

Recently published findings from researchers based at Cardiff University have uncovered the previously unknown influence of a gene in ensuring healthy brain development. They believe that this gene is a high risk factor for mental illness including schizophrenia, major clinical depression and bipolar disorder and could lead to more accurate diagnose of these diseases. To discuss their findings further we spoke to Prof. Kevin Fox, project lead on the study.

JR: Researchers at Cardiff University have recently published research which identifies a key gene in the development of Schizophrenia. Could you explain what the function of this gene is?

KF: DISC1 is a widely expressed and multi-functional protein which has several crucial roles at different stages of development. It is important for cell division, for cell migration and for the growth of neuronal processes called dendrites. We have looked at just one of these functions where DISC1 organises dendrites and the synapses on those dendrites. Our study focussed on disrupting the interactions of DISC1 with other key proteins at a time when many neurons are undergoing rapid proliferation and forming key synapses that would seem to determine many aspects of their performance throughout their lifetime.

We found that over-expressing the C-terminal of the DISC1 protein for a period of 1-2 days at the end of the first postnatal week caused both short-term and long-term deficits in the ability of cortical synapses to undergo plasticity. The most visible consequence of this was the inability of adult mice with transient DISC1 dysfunction to undergo the normal process of experience-dependent plasticity, where the brain “rewires” itself in response to a long-term change in stimulus. We study such changes using the barrel cortex, the primary sensory area of many rodents that is functionally and anatomically representative of the arrangement of whiskers on the rodent’s face. Trimming the whiskers causes a change in the input to this area of cortex, and a subsequent re-weighting of the responses to both the trimmed and non-trimmed whiskers. This simple and well-defined circuit thus becomes a powerful tool for assaying the functionality of cortical plasticity.

We believe that the section of DISC1 protein we over-express is involved in crucial interactions with other trafficking and structural proteins e.g. NUDEL and LIS, and that disruption of these interactions at postnatal day 7 is enough to hamper neuronal plasticity for life, revealing a critical period of plasticity itself. The gradual natural amelioration of several plasticity mechanisms through life means that this deficit may not be apparent until adulthood. This perhaps explains the delay in onset of many psychiatric conditions until post-adolescence.

JR: How does your research build on what was already known about the genetics behind the disease?

KF: There was a lot known about the genetics before from the Porteous group studying a Scottish family with a high incidence of mental health problems (not limited to just schizophrenia). A frameshift mutation was also found in an American family by researchers at Johns Hopkins and a Finnish cohort with DISC1 mutation has also been studied (Peltonen group). These were all strong correlations, but comparatively little was known about what DISC1 did in the brain despite some elegant studies involving various mutations. We have shown that it is vital in early development for generation of normal synapses in adulthood, with very short-term dysfunction leading tod evastating long-term consequences. Our research is based on function, on the development and behaviour of cortical circuitry, and so builds on and is complementary to the genetic studies that have already been performed.

JR: Mouse models were used in your research, are you confident that your findings would be mirrored in equivalent human experimentation?

KF: This is a good question, obviously the goal of our research is to provide information that can be used in the identification and treatment of psychiatric disease in humans. The basic circuitry of the cortex and the function of the neurons within it is known to be similar across a range of mammalian species, with the only real differences being in the level of complexity and the specialisation of different cortical areas. We know that there is a high degree of homology between proteins found in murine synapses and in human synapses, and that interference with a range of mental disorder risk genes identified in humans leads to network disruption in mice (e.g. MacLaren et al, 2011). It is difficult to directly test cortical synaptic function in human patients, however there is a large body of evidence to suggest that schizophrenic patients exhibit cognitive deficits, which would be expected if their cortical circuitry was malfunctioning in a similar manner to our experimental model.

JR: How do you hope the findings of your research will be applied to develop an effective therapeutic for Schizophrenia?

KF: Firstly the diagnosis of mental health disorders is primarily accomplished by matching patients to an agreed list of symptoms, little is able to be done in terms of actual biological tests. By increasing our knowledge of the genes and proteins involved in these diseases our first hope would be to improve and refine diagnosis by providing clinicians with solid biomarkers to investigate.

With that in mind, our study would suggest that these disorders may be explained by a deficit in neuronal plasticity. Perhaps increasing plasticity in adult schizophrenia patients may allow themal functioning cortical circuits to adjust towards a state found in those without schizophrenia, compensating for the developmentally produced defect in plasticity caused by mutant DISC1.

Prof. Kevin Fox was speaking to Jack Rudd, Editor for Technology Networks.