Schizophrenia affects around 1% of the global population and can cause paranoia, hallucinations and a breakdown in patients’ thought processes, with a huge impact on their ability to carry out everyday tasks. Around 50% of people who suffer with the condition attempt suicide.
There are currently relatively few treatments for the condition – and the drugs that are available can have unwanted side effects, such as shakiness, weight gain and decreased libido. However, genetics may hold the key to developing more effective treatments. My colleagues and I recently discovered that one specific gene may allow us to decode the function of all genes involved in the disease. This “Rosetta Stone” gene has revealed a period early in the brain’s development when treatments may be most effective in preventing schizophrenia manifesting in the first place.
Mental health conditions are among the most challenging medical problems we face as scientists, partly because of the complexity of the biology underlying thought processes and partly because studying a living brain is very difficult. However, recent studies have begun to make some headway in understanding the biology of mental health conditions by looking at the gene mutations carried by people diagnosed with such problems.
Gene mutations are present in all the cells in the body and can be examined by taking a blood sample. We now know that many of the genes involved in mental health conditions carry instructions for creating the proteins in the brain’s synapses. These are the connections between neurons that allow them to communicate with one another.
But despite knowing about hundreds of mutations associated with schizophrenia, we are relatively in the dark about what they all do. Many different mutations can give rise to the same apparent condition. On the other hand, no single gene mutation necessarily gives rise to a discernible mental health problem.
One gene we do have some certainty about is known as “disrupted in schizophrenia gene 1” (DISC1). It relates to a protein that, when mutated, can give rise to a number of mental health conditions including schizophrenia, bipolar disorder, major clinical depression and autism.
While schizophrenia may be inherited, the probability of inheritance from a mutation carried by one parent alone is relatively low. In contrast, DISC1 mutations are highly penetrant, meaning that carrying the mutation is highly likely to give rise to the characteristic problem.
This makes DISC1 a very useful experimental tool, because if a laboratory animal such as a mouse carries the mutation, it is highly likely to exhibit the functional problem and to give rise to offspring with the same problem. Studying DISC1 solves two problems at once: we do not need to look at human neurons because we can use mice instead – and we only need a single mutation rather than the several gene mutations that normally give rise to the condition.
In our studies on DISC1 mice, we have found that the gene has an important function during an early period of brain development. If you impair the function of DISC1 for just two days during the second week after birth, the animal grows up with a lack of brain plasticity (the ability to change neural pathways over time) in the synapses that were trying to form at the time.
Different parts of the brain may mature at different times, but most cortical areas go through a similar sequence of development. Therefore, different areas are all likely to go through the vulnerable period at some point in their development. One of the challenges for the future is to discover what these “critical periods” are for different areas of the brain.
So how can studying DISC1 help us decode what is going wrong with other genes in schizophrenia? Our thought is that we may have identified a critical period in development, which is a common vulnerable period for all – or at least many – of the genes identified as risk factors in schizophrenia. DISC1 mutations have also been linked to autism and Asperger’s syndrome, suggesting that the developmental effects of DISC1 could also be important for understanding these mental health conditions.
The interaction between gene mutations and brain development may have made it difficult to understand how the long list of risk factors can cause problems in the adult brain. Now we know when to study the function of other risk factors and what the outcome is for adult function. We hope this will allow us to throw some light on what the other genes involved in schizophrenia are doing (or doing wrong) during development to give rise to the debilitating condition of schizophrenia.