Researchers have successfully eliminated one of the major symptoms of schizophrenia in mice that were genetically predisposed to develop the condition. Outlining their work in the journal Neuron, the study authors describe how the manipulation of a single protein enabled them to prevent mice from experiencing memory deficits, which is often associated with schizophrenia.
Affecting more than 20 million people worldwide, schizophrenia is a long-term mental illness produced by deficient connectivity between brain cells – or neurons – leading to a range of symptoms such as hallucinations and emotional dysregulation. Spatial working memory, which processes short-term information about one’s immediate environment, has also been shown to be significantly impaired in schizophrenic individuals.
While the condition has been associated with a range of genetic and environmental factors, a mutation to a particular gene called 22q11.2 has been identified as the single biggest predictor of the disease, with around 30 percent of carriers becoming schizophrenic. Previous research using mice has revealed that this mutation sparks increased production of a protein called Gsk3β in the brain, which then prevents neurons from connecting to one another.
Subsequently, connectivity between brain regions called the medial prefrontal cortex (mPFC) and the hippocampus (HPC) is reduced, leading to an impaired spatial working memory. However, in a recent study, inhibition of Gsk3β with a drug restored the development of neurons in the mPFC and HPC of mice with this mutation, suggesting that the process can be reversed.
Schizophrenia has been associated with a reduction in the number of connections between neurons in the brain. Leigh Prather/Shutterstock
Building on this information, the researchers wanted to investigate if this effect actually translated to a reduction in schizophrenia symptoms. To test this, they created models of schizophrenia by engineering mice to carry the genetic mutation, and implanted electrodes into their brains in order to measure their activity. Several doses of a compound called SB, which inhibits Gsk3β, were administered to these mice during the first 28 days of their lives, since this early period of brain development is considered crucial for the establishment of key neural connections.
Between the ages of three and five months, the mice were subjected to a memory test in which they were required to navigate a simple maze in order to obtain a reward. Researchers recorded how long the mice took to learn the correct route well enough to achieve a 70 percent success rate, and found that those treated with SB reached this level just as quickly as non-mutant mice, while the untreated mutants took significantly longer.
At the same time, data recorded by the electrode implants revealed that connectivity between the mPFC and HPC was restored to non-schizophrenic levels in mice that had received SB, and that signaling pathways between these two brain regions were activated during the maze task. This would appear to indicate that not only is communication between these regions key to spatial working memory, but that by inhibiting Gsk3β it is possible to restore this connectivity and eliminate memory deficits.
Though these results are exciting, several questions remain. For instance, while the mice were treated soon after being born, at a time when certain crucial neural connections were being formed, schizophrenic symptoms in humans don’t usually become apparent until late adolescence. It is therefore unknown if inhibiting Gsk3β at this late stage – long after it has had a chance to disrupt early neural development – can produce the same effect.
