Picking Apart Schizophreniaby Andy Murray, PhD | February 26, 2016
In A Beautiful Mind , John Nash, played by Russell Crowe, is immersed in a fantasy world of conspiracy and paranoia. All of this we later learn is a product of his mind and a symptom of his untreated schizophrenia.
This story is a powerful example of what’s known as the ‘positive’ symptoms of schizophrenia, meaning that they are in addition to our normal everyday experience. This is contrasted by ‘negative’ symptoms, such as social withdrawal and depression. The observation of these seemingly opposing groups of symptoms form the basis of an argument that schizophrenia, rather than being a single disease, is in fact a collection of different disorders each with their own specific set of symptoms.
What some patients consider the most debilitating group of symptoms though, are not the hallucinations or social anxiety, but are actually a third group, which affects cognition (or the mental processes of memory, perception or judgment).
Cognitive problems include issues with working memory or how well you can hold information in your mind for short periods, and something called “cognitive flexibility”.
As an example of everyday cognitive flexibility, think about how you may park your car in the same spot every day. One day though your usual space is taken and your car has to be parked on the next block. Your memory is normally flexible enough to suppress your old memories (of where your car is usually parked), in favor of today’s parking spot, but someone with schizophrenia may struggle with this. Think how difficult daily life would be if you could not remember where you had put your keys moments before, where your car was parked or what needed to be picked up at the supermarket. This is why cognitive symptoms in schizophrenia can be so debilitating, and this is made even more problematic when we consider that currently available medications can treat positive and negative, but not cognitive symptoms.
A recent study in Scientific Reports goes some way to strengthen the argument that schizophrenia is a group of distinct disorders, and that cognitive problems are related to the dysfunction of specific neural circuits. For full disclosure, I was a researcher on the study and I am one of the authors of the paper.
In this study, we looked at the function of a particular type of neuron in the prefrontal cortex of the mouse brain. The prefrontal cortex is part of the brain’s frontal lobe and is often linked with cognition and complex thought and many studies have found that the prefrontal cortex malfunctions in schizophrenics. In this area one particular type of neuron has been repeatedly found to be damaged, those known as parvalbumin-positive interneurons, or PVIs for short.
PVIs are an inhibitory type of neuron, meaning they can block the electrical firing in neurons to which they are connected. By inhibiting groups of neighboring neurons PVIs are believed to “tune” the larger, excitatory, principle neurons in the prefrontal cortex. In this way then, PVI dysfunction in schizophrenia could lead to a malfunctioning prefrontal cortex and therefore cognitive problems. This idea though has been very difficult to test directly. It can be tricky to study the function of one particular type of neuron in the prefrontal cortex, without having undesired effects on the numerous other types that are found in the same area.
We were able to devise a method to block the synaptic transmission (the mechanism by which neurons communicate with each other) only in PVIs in the prefrontal cortex of mice. Doing this meant that we were able to look at different types of behaviour that were closely linked to the positive, negative and cognitive symptoms of schizophrenia. From previous studies we knew that less selective damage to the prefrontal cortex would lead to symptoms in all of the positive, negative and cognitive groups.
After blocking PVI synaptic transmission, we examined how sociable the mice were with other animals, as a means to assess their negative-like symptoms. They showed similar levels of interaction when compared to a control group. We took this to mean that PVIs are not involved in schizophrenia’s negative symptoms. Similarly, when we looked to see if they were hyperactive, a correlate of positive symptoms, their activity was normal. So, neither positive nor negative symptoms were created when we disrupted PVIs.
The story was a little different when we looked for cognitive problems. When placed in a maze the animals were unable to recall where they had been just moments before. Then when they needed to suppress a strong memory of a particular place in a different maze (where they would normally find some food) in favour of a new location, they were very slow at learning this new place. It seemed then that disrupting PVIs in the prefrontal cortex resulted in problems with working memory (where have I just been?) and cognitive flexibility (why is the food not in the same place it usually is?). The important part though, is that these were the only problems that they had, otherwise they displayed completely normal behaviour.
If we can block the actions of one type of neuron in one brain area and recreate just one set of schizophrenia symptoms then this supports the idea that schizophrenia is multiple disorders, perhaps with different neural circuits involved in each. Indeed, other studies have implicated different types of neurons in positive symptoms. Here, the malfunction of the chemical messengers, or neurotransmitters in the brain, called dopamine, could underlie problems like hallucinations.
While we hope that this study helps to unravel the complicated neurobiology of schizophrenia, there is obviously still a long way to go. It is extremely difficult, and not necessarily accurate, to relate the behaviour of a mouse to the complex feelings and emotions of a schizophrenic patient. But, by picking apart the neural circuits that map to different aspects of the disease we can gain both a greater understanding of the disease itself and the potential to generate more symptomatically targeted therapies in the future.
Lewis, D. (2014). Inhibitory neurons in human cortical circuits: substrate for cognitive dysfunction in schizophrenia Current Opinion in Neurobiology, 26, 22-26 DOI: 10.1016/j.conb.2013.11.003
Murray, A., Woloszynowska-Fraser, M., Ansel-Bollepalli, L., Cole, K., Foggetti, A., Crouch, B., Riedel, G., & Wulff, P. (2015). Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility Scientific Reports, 5 DOI: 10.1038/srep16778
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