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Abnormal neural activity linked to schizophrenia

Neuroscientists have discovered abnormal neural activity in the brain that may cause people with schizophrenia to experience unorganized thought processes, according to a study published in the journal Neuron.

Researchers from the Massachusetts Institute of Technology (MIT), led by Susumu Tonegawa, conducted a mouse study in which they found that mice lacking a brain protein called calcineurin experienced hyperactive brain-wave oscillations in the hippocampus when resting.

According to the researchers, previous studies have identified mutations in the gene for calcineurin in schizophrenic patients. Over 10 years ago, the researchers decided to create mice who were lacking this gene in their forebrain.

The researchers found that these mice showed many symptoms of schizophrenia that is present in humans, including impaired short-term memory, attention deficits and abnormal social behavior.

For this most recent study, the researchers monitored the electrical activity of individual neurons in the hippocampus of the mice, while they ran along a track.

Previous research has shown that normal mice have "place cells" present in their hippocampus, the study authors note.

These cells demonstrate a "mental replay" of specific locations along a running track, firing in sequence as a mouse rests from the running course and when they are sleeping. These mental replays are linked to very high frequency brain-wave oscillations known as "ripple events."

Lack of calcineurin impairs 'place cells'

However, when monitoring the mice lacking calcineurin, it was found that their brain activity was normal while they were running on the track, but it appeared stronger and more frequent when they rested, compared with normal mice.

Additionally, the researchers found that the firing of the place cells was "abnormally augmented" and in no specific order, suggesting that the mice were unable to replay the route they had just run on the track.

Junghyup Suh, a research scientist at the Picower Institute at MIT and a lead author of the study, explains:

"We think that in this mouse model, we may have some kind of indication that there's a disorganized thinking process going on.

During ripple events in normal mice we know there is a sequential replay event. This mutant mouse doesn't seem to have that kind of replay of a previous experience."

Hyperactivity 'disrupts default mode network'

From these results, the researchers hypothesize that the role of calcineurin in normal mice is to abolish the synapses - the connections between neurons - in the hippocampus.

However, they say that mice lacking calcineurin appear to experience long-term potentation (LTP) - a long-term signal transmission between neurons - which makes synapses stronger. Furthermore, they note that the opposite effect to LTP - long-term depression (LTD) - is suppressed.

"It looks like this abnormally high LTP has an impact on activity of these cells specifically during resting periods, or post exploration periods. That's a very interesting specificity. We don't know why it's so specific," says Prof. Tonegawa, Picower professor of Biology and Neuroscience.

The researchers also believe that the abnormal hyperactivity discovered in the hippocampus of the mice lacking calcineurin could show a disruption of the brain's default mode network (DMN). This is a communication network that connects the hippocampus, prefrontal cortex and other parts of the cortex.

They note that in a normal person, the network is more active when a person rests in between tasks which involve focus on specific goals or activities.

But in those who are schizophrenic, the default mode network is hyperactive before and during tasks that need the brain to focus, meaning that patients underperform in these types of activities.

"Therefore," the study authors say, "our findings provide a novel link that SWR (sharp-wave ripple) activity may constitute a point of convergence across disparate schizophrenia models, and a new insight into the neural basis of the cognitive disorder."

They add that further studies are needed in the mice lacking calcineurin in order to find out more about how the default mode network is linked to schizophrenia.

Junghyup Suh told blog:

"Our study now provides a novel way to look into the actions of current antipsychotic drugs or treatments. Any neurobiological approach that can calm down the DMN may open up new avenues in alleviating the symptoms and curing this mental disorder."

blog recently reported on a study detailing the discovery of genes that may cause schizophrenia.

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