How much was previously known about the 'disrupted in schizophrenia-1' DISC-1 gene?
The DISC-1 gene has been studied intensively over the years because people with mutations in DISC1 have a high likelihood of mental illness.
DISC-1 was known to be associated with schizophrenia, bipolar disorder, major clinical depression and autism.
Research up until now has mainly focused on its molecular signalling and its role in cell division, cell migration and intracellular transport.
What did your recent research reveal about the influence of DISC-1 in ensuring healthy brain development?
Our studies showed that the interaction of DISC1 with Lis and Nudel was vital during an early period of development for synaptic plasticity to be present in adulthood. We identified a very short time window in the second post-natal week when normal DISC1 function is required.
Without normal DISC1/Lis/Nudel interactions in this critical period of development the synapses and dendrites did not mature properly. In adulthood, this meant that they couldn't undergo plasticity.
Why is brain plasticity so important?
Plasticity is thought to underlie many important functions of the brain. Synaptic plasticity allows neurons to encode and store information and in this way underlies learning and memory.
Plasticity allows neuronal circuits to form connections in the brain and to adapt behaviour to new circumstances.
What impact does lacking brain plasticity have on the ability to form thoughts and perceive the world?
We do not know enough about this to be certain because we cannot easily measure thoughts and perceptions in mice. However, we think that plasticity is important for forming stable sets of neuronal connections that allow for persistent neuronal activity in the brain.
Persistent neuronal activity in turn allows information to be held “in mind” during performance of a task, such as making a decision. However, these are conjectures at present and need to be tested more fully.
At what point in the brain's development does preventing DISC-1 from binding with molecules 'Lis' and 'Nudel' affect the brain's plasticity?
During the second postnatal week (P7-13) in mice. Mice are born relatively immature compared with humans, so this is likely to correspond to a period in the last trimester in humans.
Does preventing DISC-1 from binding with these molecules when the brain is fully formed have any effect on its plasticity?
No. This is one of the fascinating things about it. It is possible that it has some effect that we have not measured, but we find the manipulation that has such a big effect during development has no effect on plasticity if initiated in adulthood.
Why do you think this seven-day window occurs and do you think it will be possible to treat people during this critical period moving forwards?
I think it occurs because the synapses are forming during this period. It may be difficult though not impossible to treat people during this period in the future, but people may not want the treatment then because they would not be certain that the defect would manifest itself later in adulthood.
It may be better to try and find a treatment for adults, because then that patient would know they definitely needed treatment and could benefit.
Do you think it will be possible one day to reverse the problem during adulthood by returning plasticity to the brain?
Yes I think this might be possible. We found that one form of plasticity was affected in the DISC1 mutants known as long-term potentiation (LTP), but other juvenile forms of plasticity were not.
The juvenile forms of plasticity are gradually lost with age, but if we could reinstate them in adulthood, it might ameliorate the loss of LTP.
Where can readers find more information?
Our recent paper was published in Science: http://www.sciencemag.org/content/349/6246/424.short. More information can be found on schizophrenia on The Society for Neuroscience's Brain Facts website:
Schizophrenia Research Forum also has a number of articles on DISC1 and other factors involved in schizophrenia: http://www.schizophreniaforum.org/
About Kevin Fox
Kevin Fox PhD MAE FMedSci is a Professor of Neuroscience and a member of the School of Biosciences and the Neuroscience and Mental Health Research Institute at Cardiff University. His research program is funded by the MRC in the UK. He has published extensively on the molecular and cellular mechanisms underlying plasticity in the visual and somatosensory cortex. He has served as the deputy chair of the MRC's Neuroscience and mental health board and is a fellow of the Academy of Medical Sciences.
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