Schizophrenia is a long-term mental health problem with a complex of symptoms ranging from unorganized thinking or speech to hallucinations. The causes—it seems—are equally complex, with a combination of physical, psychological, environmental and genetic factors implicated. A group of researchers from Duke University decided to focus on just one of these genetic factors, and found that it was linked to three crucial changes in the brain.
The study, published in the journal Nature Neuroscience, linked together three possible ideas for the cause of schizophrenia that were previously thought to be unrelated. This new insight into the molecular basis of schizophrenia offers hope for new treatments that are more targeted to the underlying causes of the disorder, rather than just treating the symptoms.
The researchers decided to look at how one gene, Arp2/3, contributed to the formation of mental disorders. They chose this particular gene because it is known to be important in governing the formation of the connections between neurons, called synapses, and has also been linked to various mental health conditions. They then genetically modified mice to lack the Arp2/3 gene.
Surprisingly, the modified mice displayed schizophrenia-like behaviors. Furthermore, like humans, the animals worsened over time, and when then given antipsychotic medicine, some of the animals’ symptoms were relieved.
When the team, led by Scott Soderling, investigated whether there were any physical or chemical changes in the brain linked to the behaviors seen in the Arp2/3 gene-deficient mice, they discovered three brain abnormalities—all originally considered to be unlinked—that also appear in humans with schizophrenia.
Firstly, they found that cells in the brain's frontal area—the region responsible for planning and decision-making—had fewer than normal "dendritic spines." These are the branches that help connect neurons to each other. As the mice aged, they lost more and more of these spines. This is known as the ‘spine pruning theory.’
Secondly, consistent with people suffering schizophrenia, they discovered that the mice lacking Arp2/3 also had hyperactive neurons in the same frontal region of the brain. It was originally thought that hyperactive neurons were incompatible with the ‘spine pruning theory.’ However, the neurons of the modified mice were found to be able to bypass the spines, which act as a filter to keep hyperactive neurons in check. As a consequence, the cells went into overdrive.
A third theory suggested that too much dopamine within the brain played a major role in schizophrenia. This was backed up by the fact that a major drug used to treat mental disorders, haloperidol, works by blocking dopamine transmission. The researchers found that the hyperactive neurons in the front of the mice's brains made them dump large amounts of dopamine.
"The most exciting part was when all the pieces of the puzzle fell together," explained Soderling. "When Dr. Kim and I finally realized that these three outwardly unrelated phenotypes—spine pruning, hyperactive neurons and excessive dopamine—were actually functionally interrelated with each other, that was really surprising and also very exciting for us."
With the drug haloperidol acting as one of the main treatments to help tame the symptoms of schizophrenia by reducing the amount of dopamine within the brain, this new research goes to show that rather than being the cause of the problem, the excess dopamine is actually the result of a series of misfirings. It is hoped that this might lead to new treatments that interrupt this cascade, before it manifests in debilitating psychiatric symptoms.