The role of DISC1 in synaptic function and circuit formation during critical periods of cortical development

Mental Health conditions are among the most challenging medical problems we face. The cost to society and the burden on families of are extremely high. Costs were estimated to be £6.7 billion pounds in England alone in 2004/5. The cost of schizophrenia alone is very high to the individuals and their families and some 50% of schizophrenics attempt suicide. Recent genetic studies have revealed a number of candidate molecules that play a role in producing mental health conditions. A large number of these molecules are found in synapses in the brain. Synapses are the structures that allow brain cells (or neurones) to communicate with one another. One such molecule present at the synapse is known as Disrupted in Schizophrenia 1, or DISC1, and was discovered by Kirsty Millar and David Porteus and colleagues in Edinburgh. Having a mutation in this gene can increase the chances of suffering from one of a number of mental disorders including schizophrenia, bipolar disorder, recurrent major depression and autism. We have recently discovered that DISC1 affects synaptic plasticity. Synaptic plasticity is the ability of synapses to change their transmission properties and hence alter the "loudness" or gain with which cells communicate with one another. Synaptic plasticity is thought to be responsible for memory. A loss of synaptic plasticity could account for the deficits in working memory (and cognitive function in general) seen in these debilitating conditions. We found that DISC1 needs to be working properly during a short period of a week or so following birth to prevent the loss of synaptic plasticity in part of the brain known as the cerebral cortex in adulthood. In the present study, we propose to identify as closely as we can what exactly goes wrong in development of the cortex when DISC1 malfunctions and results in a loss of synaptic plasticity in the adult. We will initially study this process in a simple part of the cortex known as the barrel cortex, because its organisation is relatively straightforward and a lot is known about it. We can then look to see if similar developmental problems occur in other parts of the cortex, like the prefrontal cortex, which is thought to be particularly problematic in schizophrenics. Understanding how the connections made between neurones in the cortex are disrupted by DISC1 will help us to formulate remedies to treat these conditions.

We will conduct four main experiments on DISC1-cc mutants, where the trangene product (amino acids 671-852 of DISC1) is made available within the cell by administration of tamoxifen. The transgene is constitutively expressed in excitatory forebrain neurones under the control of the CaMKII promoter. Tamoxifen binds to the ligand binding domain (LBD) of the oestrogen receptor (which is made as a fusion protein with DISC1-cc). The LBD does not bind natural oestrogen. Binding tamoxifen causes LBD-DISC1-cc to dissociate from heat shock proteins and the proteasome degradation pathway and is therefore free to interact with DISC1's natural binding partners such as Lis and Nudel. The gene is active for a period of between 6 and 24 hours following a single tamoxifen injection. In these studies we activate DISC1-cc at various time points from the second postnatal week to one month of age and study the effect on 1. experience-dependent plasticity in the barrel cortex 2. dendritic development in layer III, IV and layer V neurones of barrel cortex and prefrontal cortex 3. input circuits to layer III and V neurones and 4. the synaptic plasticity properties of the layer IV to III pathway, including spike timing LTP, experience-dependent GluR1 insertion and the natural development of synaptic transmission (NMDA/AMPA ratios, conversion of silent to active synapses) during the second postnatal week. In each case DISC1-cc will only affect circuit development from a point in development beyond the end of neocortical neuronal migration.

Pathways to Impact

1. Background
The work proposed in this application will provide novel and detailed information on the consequences of DISC1 malfunction during development of the cortical circuit. DISC1 is a molecule that is implicated in schizophrenia and is involved in several developmental processes in the brain. Knowledge gained will help researchers understand how the DISC1 molecule can give rise to the symptoms of schizophrenia and other mental health disorders. At present it is not known how DISC1 can lead to impairments in cognitive function. By understanding how the cortical circuit develops abnormally, researchers in the field will be able to understand the cortical circuits responsible for particular cognitive functions and begin to envisage ways of remedying the deficits.

2. Who might benefit from this research and how?
The earliest beneficiaries of this research would be those in academia and industry. The longer-term beneficiaries would be the general public. Academics in the UK and abroad will benefit because the research findings should have implications for understanding development of the cerebral cortex, the role of particular circuits in types of cognition and the means by which genetic defects can affect neuronal circuit formation. Industry, or more specifically, pharmaceutical companies can benefit in two main ways; first, because this study should help to understand how genetic mutants can be made to study and understand psychiatric conditions. Second, because, by identifying the defective anatomical pathways in the cortex and understanding how they function, the receptors can be identified that might be available for drug treatment. The general public can benefit both directly and indirectly from this research. The hope is that direct benefits will accrue to people suffering from schizophrenia and bipolar disorder and their families as the research is aimed at understanding the etiology of the disease and hence finding a cure. Indirect benefits will accrue to society in general as a result of avoiding or reducing the direct cost of coping with these individuals and reducing or avoiding the indirect costs to society such as loss of productivity in the workforce and impositions on the criminal justice system. Together these costs are extremely high (estimated as £6.7 billion in 2005 in England alone).

3. What will be done to ensure that potential beneficiaries have the opportunity to engage with this research?
Academics and members of pharmaceutical companies will be able to engage with this research through lectures and presentations at national and international meetings and from publications in neuroscience journals. Publications will be in peer reviewed open access journals and therefore widely available. Members of the public will be able to engage with the research through the activities organized by the Neuroscience and Mental Health Research Institute at Cardiff University once the research reaches fruition. However, health benefits will only become relevant at a stage beyond the small step envisaged in the current research program and therefore engagement with this group will naturally occur later in the overall program of research.