Tag Archives: #bipolardisorder

Disrupted Biochemical Pathway in the Brain Linked to Bipolar Disorder (Neuroscience)

Bipolar disorder affects millions of Americans, causing dramatic swings in mood and, in some people, additional effects such as memory problems.

While bipolar disorder is linked to many genes, each one making small contributions to the disease, scientists don’t know just how those genes ultimately give rise to the disorder’s effects.

However, in new research, scientists at the University of Wisconsin–Madison have found for the first time that disruptions to a particular protein called Akt can lead to the brain changes characteristic of bipolar disorder. The results offer a foundation for research into treating the often-overlooked cognitive impairments of bipolar disorder, such as memory loss, and add to a growing understanding of how the biochemistry of the brain affects health and disease.

The Cahill lab and their colleagues at Michigan State University published their findings March 24 in Neuron.

Akt is a kinase, a type of protein that adds tags of the molecule phosphate to other proteins. These phosphate tags can act as on or off switches, changing how other proteins work, ultimately influencing vital functions. In neurons, those functions can include how cells signal to one another, which can affect thinking and mood. When the Akt pathway is revved up, a lot of other proteins get phosphate tags. When it’s quieter, those phosphate tags are absent.

The researchers discovered that men with bipolar disorder have reduced activity of this pathway, known at Akt-mTOR, in a brain region crucial for attention and memory. And when the researchers disrupted the pathway in mice, the rodents developed memory problems and crucial brain connections withered away, simulating changes in humans with bipolar disorder.

“This loss of Akt pathway function in people with bipolar disorder is probably contributing to cognitive impairment,” says Michael Cahill, a professor of neuroscience in the UW–Madison School of Veterinary Medicine, who led the research. “The idea is that maybe we can target pathways like this one pharmacologically to help alleviate core symptoms of bipolar disorder.”

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

By measuring the number and variety of phosphate tags on proteins controlled by Akt in the tissue samples, the researchers could get a sense of the overall activity of the Akt-mTOR pathway.

Although they were originally expecting to see the biggest changes in patients with schizophrenia — which has the strongest genetic links to the Akt gene among the three related disorders — the researchers found that activity of the Akt-mTOR pathway was diminished in just one group of patients: men with bipolar disorder without psychosis.

“It was very different than we thought, which is kind of a good example of how in science you don’t really know what you’re going to get,” says Cahill.

After seeing this correlation between bipolar disorder and a quieter Akt pathway, Cahill’s group then asked what effect this diminished Akt pathway would have in the brain. To answer that question, they used viruses to deliver broken Akt proteins to the prefrontal cortexes of mice. The broken Akt proteins would override working ones, gumming up the Akt pathway.

In behavioral tests, the mice with gummed up Akt pathways demonstrated memory problems, no longer exploring changes to familiar environments.

Spending a lot of time investigating objects or other features that have changed their location is “their way of telling us that they recognize something is different,” says Cahill. “That was impaired when we disrupted the Akt pathway.”

But mice with less active Akt pathways still showed typical social behaviors, suggesting that the pathway wasn’t responsible for other high-level brain functions.

When the scientists looked in the brains of mice with diminished Akt pathways, they found that the connections that neurons use to interact with other neurons, known as dendritic spines, had withered.

Dendritic spines are like intersections between the roads that information in the brain travels on. “With the number of intersections being reduced, it’s harder to get where you want to go,” Cahill says.

That disrupting the Akt pathway in mice seemed to replicate aspects of bipolar disorder that also occur in humans — memory problems, weaker neuron connections —provides the first clear link from this gene to 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 did. Nor did people with bipolar disorder with psychosis or those with schizophrenia, despite similar genetic links between the Akt pathway and these disorders.

Untangling these differences and fleshing out the path from genes to disease will require much more research. For instance, many other genes contribute to bipolar disorder, and those genes may play a larger role in these groups.

Going forward, Cahill’s lab plans to follow individual circuits in the brain to discover just how the Akt pathway influences memory. That additional research should help unravel some of the enduring riddles surrounding bipolar disorder and how subtle genetic changes can lead to big differences in how people experience the world.

This work was supported in part by the National Institutes of Health (grants R21MH125227 and R01MH111604).

Reference: Amanda M. Vanderplow, Andrew L. Eagle, Bailey A. Kermath, Kathryn J. Bjornson, Alfred J. Robison, Michael E. Cahill, Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function, Neuron, 2021, , ISSN 0896-6273, https://doi.org/10.1016/j.neuron.2021.03.008. (https://www.sciencedirect.com/science/article/pii/S0896627321001562)

Provided by University of Winconsin–Madison

Potential Means of Improving Learning and Memory in People With Mental Illnesses (Psychiatry)

More than a dozen drugs are known to treat symptoms such as hallucinations, erratic behaviors, disordered thinking and emotional extremes associated with schizophrenia, bipolar disorder and other severe mental illnesses. But, drug treatments specifically able to target the learning, memory and concentration problems that may accompany such disorders remain elusive.

Average brain activity during a working memory task in a group of healthy subjects as measured by fMRI. The colors represent higher brain activity in the carriers of the G version of the GCPII enzyme, where brains are less efficient at performing the task, compared with those carriers with the A version of the enzyme. ©Bigos laboratory

In an effort to find such treatments, Johns Hopkins Medicine researchers report they have identified a genetic variation in the brain tissue of a subset of deceased people — some with typical mental health and some with schizophrenia or other psychoses — that may influence cognition and IQ. In the process, they unearthed biochemical details about how the gene operates.

Results of their work, described in the Dec. 1 issue of the American Journal of Psychiatry, could advance the development of drugs that target the enzyme made by this gene, and thus improve cognition in some people with serious mental illnesses or other conditions that cause reduced capacity in learning and memory.

Typical antipsychotic medications that treat schizophrenia symptoms regulate the brain chemical dopamine, a transmitter of nerve impulses associated with the ability to feel pleasure, think and plan, which malfunctions in patients with the disorder. However, previous genetic studies have also shown that another brain chemical signal transmitter, glutamate, a so-called “excitatory” chemical associated with learning and memory, plays a role as well. Another so-called neurotransmitter in this process, N-acetyl-aspartyl-glutamate (NAAG), specifically binds to a protein receptor found on brain cells that has been linked to schizophrenia, but how it impacts this disorder is unknown.

The research of clinical pharmacologist Kristin Bigos, Ph.D., assistant professor of medicine at the Johns Hopkins University School of Medicine, sought to explore more deeply the role of NAAG in cognitive impairment with the goal of eventually developing therapies for treating these learning, memory or concentration problems.

Using tissues gathered from a repository of brains from deceased donors belonging to the Lieber Institute for Brain Development, Bigos and her team measured and compared levels of certain genetic products in the brains of 175 people who had schizophrenia and the brains of 237 typical controls.

Bigos and her colleagues specifically looked at the gene that makes an enzyme known as glutamate carboxypeptidase II (GCPII), which breaks down NAAG into its component parts ? NAA and glutamate. In the brains of people with schizophrenia and in the typical controls, they found that carriers of this genetic variant (having one or two copies of the gene variation) had higher levels of the genetic product that makes the GCPII enzyme.

In the gene for the enzyme, the only difference in the versions was a single letter of the genetic code, either G or A (for the nucleotide bases guanine and adenine). If people had the version of the gene with one copy of G, then the tissue at the front of their brain ? the seat of cognition ? had 10.8% higher levels of the enzyme than those who had the version of the gene with A, and if people had two copies, they had 21% higher levels of the enzyme.

To see if this genetic variation in GCPII controlled the levels of NAAG in the brains of living people, the researchers measured levels of NAAG in the brain using magnetic resonance spectroscopy, which uses a combination of strong magnetic field and radio waves to measure the quantity of a chemical in a tissue or organ.

In this experiment, they focused on 65 people without psychosis and 57 patients diagnosed with recent onset of psychosis, meaning many of them were likely to eventually be diagnosed with schizophrenia, at the Johns Hopkins Schizophrenia Center. Participants averaged 24 years of age, and 59% were men. About 64% of participants identified as African American, and the remaining 36% were white.

The researchers found 20% lower levels of NAAG in the left centrum semiovale — a region of the brain found deep inside the upper left side of the head — in the white participants both with and without psychosis who had two copies of the G version of the enzyme compared with other white people who had the A version.

To see if having the G or A version of the gene plays a role in cognition, the researchers tested IQ and visual memory in the healthy participants and those with psychosis, both white and African American. They found that people with the most NAAG in their brain (in the top 25%) scored 10% higher on the visual memory test than those in the bottom 25%. They also found that people with two copies of the G version of the GCPII sequence scored 10 points lower on their IQ test on average than the people with the A version of the gene, which the researchers say is a meaningful difference in IQ.

Finally, they showed that healthy carriers of the G version of the GCPII sequence had less efficient brain activity during a working memory task, as measured by functional MRI, by at least 20% compared with those people with the A version of the gene.

“Our results suggest that higher levels of the NAAG are associated with better visual and working memory, and that may eventually lead us to develop therapies that specifically raise these levels in people with mental illness and other disorders related to poor memory to see if that can improve cognition,” says Bigos.

Additional authors on the study include Caroline Zink, Peter Barker, Akira Sawa, Min Wang, Andrew Jaffe, Joel Kleinman, Thomas Hyde, Kayla Carta and Marcus van Ginkel of Johns Hopkins Medicine, and Daniel Weinberger, Henry Quillian, William Ulrich, Qiang Chen, Greer Prettyman and Mellissa Giegerich of the Lieber Institute for Brain Development.

This work was supported by the Lieber Institute for Brain Development, the National Institutes of Mental Health (MH092443, MH094268, MH105660 and MH107730) and the National Institute on Drug Abuse (DA040127).

Some patient or volunteer recruitment costs were supported by the Mitsubishi Tanabe Pharma Corporation.

Provided by Johns Hopkins Medicine