Researchers identify one of the key mechanisms of bipolar disorder

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Bipolar disorder, causing erratic mood swings and, in some people, additional effects such as memory problems, affects millions of people around the world. While bipolar disorder is linked to many genes, each making a small contribution to the disease, scientists are not sure exactly how these genes ultimately cause the effects of the disorder. However, in a recent study, a team of neurobiologists managed to identify one of the key molecular pathways that cause some symptoms of bipolar disorder.

In new studies, researchers at the University of Wisconsin-Madison have found for the first time that disturbances in a particular protein, called Akt, can lead to brain changes characteristic of bipolar disorder. The findings provide a basis for research into the treatment of the often overlooked cognitive impairments of bipolar disorder, such as memory loss, and add to a growing understanding of how brain biochemistry affects the body.

Akt is a kinase, a type of protein that adds phosphate groups to other proteins. These phosphate markers can act as on / off switches, altering the functioning of other proteins, ultimately influencing vital functions. In neurons, these functions can include the way cells signal to each other, which can affect thinking and mood. When the Akt pathway is accelerated, many other proteins receive phosphates. And when it is reduced, few phosphate groups are added.

The role of the Akt pathway in bipolar disorder

Researchers have found that men with bipolar disorder have reduced activity of this pathway, called Akt-mTOR, in a region of the brain crucial for attention and memory. And when researchers disrupted this pathway in mice, rodents developed memory problems and crucial brain connections were neutralized, mimicking changes in humans with bipolar disorder.

This loss of Akt pathway function in people with bipolar disorder likely contributes to cognitive impairment. The idea is that maybe we can pharmacologically target pathways like this to help alleviate the main symptoms of bipolar disorder. Says Michael Cahill, professor of neuroscience at the UW-Madison School of Veterinary Medicine.

The Akt pathway is involved in many cellular molecular pathways, including the mTOR pathway, which itself acts on several mechanisms, such as cell signaling, protein synthesis, etc. © Fei Xu et al. 2020

To assess Akt pathway activity, Cahill’s lab acquired brain tissue samples from deceased donors with schizophrenia, bipolar disorder without psychosis, and bipolar disorder with psychosis, as well as healthy donors. The tissue samples were taken from the prefrontal cortex, known to control high-level functions, which is affected by bipolar disorder and schizophrenia.

By measuring the number and variety of phosphate markers on Akt-controlled proteins in tissue samples, researchers were able to gain insight into the overall activity of the Akt-mTOR pathway. Although they originally expected to see the most significant changes in patients with schizophrenia – which shows the strongest genetic links to the Akt gene among the three associated disorders – the researchers found that the Akt-mTOR pathway activity was decreased in only one group of patients: men with bipolar disorder without psychosis.

The impact of Akt inhibition on neurons

After seeing this correlation between bipolar disorder and a quieter Akt pathway, Cahill’s group went on to find out what effect this diminished Akt pathway would have in the brain. To answer this question, they used viruses to deliver non-functional Akt proteins to the prefrontal cortex of mice. The modified Akt proteins replaced the working ones, erasing the Akt pathway.

In behavioral tests, mice with inhibited Akt pathways demonstrated memory problems, no longer exploring changes in familiar environments. But mice with less active Akt pathways still exhibited typical social behaviors, suggesting that the pathway was not responsible for other high-level brain functions.

spine dendrite neuron image
Decreased activity of the Akt pathway results in wilting of the dendritic spines used for neural communication. © Mathias De Roo

When the researchers looked at the brains of mice with reduced Akt pathways, they found that the connections that neurons use to interact with other neurons, called dendritic spines, had withered. Dendritic spines are like intersections between the routes on which information travels through the brain.

Further research needed

Disrupting the Akt pathway in mice appeared to mimic aspects of bipolar disorder that also occur in humans – memory problems, weaker neural connections – which provides the first clear link between this gene and the effects of bipolar disorder. Yet many questions remain. Women with bipolar disorder did not show the same changes in Akt-mTOR activity as men.

The same is true for people with bipolar disorder with psychosis or those with schizophrenia, despite similar genetic links between the Akt pathway and these disorders. Unraveling these differences and pinpointing the link between genes and disease will require much more research. For example, many other genes contribute to bipolar disorder, and these genes may play a larger role in these groups.

In the future, Cahill’s lab plans to follow individual circuits in the brain to find out how much the Akt pathway influences memory. This additional research should help unravel some of the lingering puzzles surrounding bipolar disorder and how subtle genetic changes can lead to big differences.

Sources: Neuron

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