anxiety_tape_1

Gene opens unique way to attack anxiety

U. CHICAGO (US) — Researchers testing the role of a mysterious gene have identified a new target for drugs designed to treat anxiety.

The study, published in the Journal of Clinical Investigation, shows that animals with multiple copies of the Glo1 gene were more likely to exhibit anxiety-like behavior in laboratory tests.

Further experiments showed that Glo1 increased anxiety-like behavior by lowering levels of methylglyoxal (MG). Conversely, inhibiting Glo1 or raising MG levels reduced anxiety behaviors.

“Animals transgenic for Glo1 had different levels of anxiety-like behavior, and more copies made them more anxious,” says Abraham Palmer, assistant professor of human genetics at the University of Chicago and the study’s senior author of the study. “We showed that Glo1 was causally related to anxiety-like behavior, rather than merely correlated.”

In 2005, a comparison of different mouse strains found a link between anxiety-like behaviors and Glo1, the gene encoding the metabolic enzyme glyoxylase 1. However, subsequent studies questioned the link, and the lack of an obvious connection between glyoxylase 1 and brain function or behavior made some scientists skeptical.

“When people discover a gene, they’re always most comfortable when they discover something they already knew,” Palmer says. “The alarming thing here was there was a discovery of something that nobody knew, and therefore it seemed less likely to actually be correct.”

Multiple copies

A 2009 study from Palmer’s laboratory suggested that differences in Glo1 expression between mouse strains were due to copy number variants, where the segment of the genome containing the gene is repeated multiple times.

To test this hypothesis, lead author Margaret Distler inserted two, eight, or ten copies of the Glo1 gene into mouse lines. She then ran experiments such as the open field test, in which researchers measure how much time a mouse spends in the center of an arena versus along the walls, to detect changes in anxiety behavior.

The results confirmed a causative role for Glo1 copy number variants, as mice with more copies of the Glo1 gene exhibited higher anxiety-like behavior in their experiments.

“It’s the first study to show that it’s the copy number variant that has the potential to change Glo1 expression and behavior,” says Distler, an MD/PhD student in the Pritzker School of Medicine’s Medical Scientist Training Program. “Our study was a physiological representation of what it means to increase Glo1 expression for anxiety.”

Rapid response to MG

The researchers then set about answering the mystery of how Glo1 expression influences anxiety-like behaviors.

The primary function of glyoxylase 1 is to metabolize and lower cellular levels of methylglyoxal, a waste product of glycolysis. Distler produced the opposite effect by injecting MG to artificially increase its levels in the brain, finding that raising MG levels quickly reduced anxiety symptoms in mice.

“Methylglyoxal changed behavior within 10 minutes of administration, which means it’s a rapid onset. It’s not changing gene expression, and it’s not having long-term downstream effects,” Distler says. “That was our first breakthrough.”

The short time course suggested that MG might have a direct effect on neuronal activity. MG also demonstrated sedative effects at high doses, a hallmark of drugs that activate inhibitory GABA receptors on neurons. In collaboration with Leigh Plant, now at Brandeis University, the researchers demonstrated that MG activated GABA-A receptors on neurons, a previously unknown inhibitory mechanism.

“It’s a completely different system that is tying neuronal inhibitory tone into metabolic activity,” Palmer says. “That’s potentially really exciting in terms of re-evaluating what we thought we knew about inhibitory tone in the CNS. It turns out now that methylglyoxal, which has been around ever since glycolysis evolved, was also acting at these receptors, and nobody knew that.”

Selective advantage

Conventionally, anxiety has been treated with drugs that activate the GABA-A receptor, such as benzodiazepines and barbiturates, which are prone to abuse and dangerous side effects. The researchers theorized that targeting the Glo1/MG interaction could provide a more selective strategy for reducing anxiety symptoms by subtly influencing inhibitory tone.

“The GABA-A receptor agents already out there have a lot of side effects, such as sedation and hypothermia, as well as a high abuse liability,” Distler says. “It’s possible that taking a Glo1 inhibitor will increase only MG levels to a certain maximum. You could have the potential for more specificity, given that you’re activating a system that’s already in place, not just dumping methylglyoxal or some other GABA-A receptor agent throughout the brain.”

Preliminary experiments with a small molecule inhibitor of Glo1 supported the theory. Injections of the inhibitor, developed by John Termini at the Beckman Research Institute of the City of Hope, reduced anxiety-like symptoms in mice.

“It’s a different way of hitting these GABA-A receptors,” Palmer says. “We have yet to determine if that’s a better way of doing it, but it’s certainly different, and it gives us a unique angle of attack on this system and potential advantages that we have yet to evaluate.”

Such a drug may also be useful in treating epilepsy and sleep disorders, where GABA-A drugs have shown success. While the therapeutic potential of manipulating this system is yet to be determined, the research clears the fog around the role of Glo1 in anxiety by adding behavioral and cellular evidence.

“What’s neat is that we started with exploratory, open-ended genetic studies in mice, and we’ve now gotten into some fundamental new physiology that nobody had appreciated or put together before,” Palmer says. “Now we’re starting to reap some of the fruit from those types of genetic studies to enrich our understanding of more classical aspects of biology.”

The research was funded by grants from the National Institute of Mental Health, the National Institute on Drug Abuse, National Institute of General Medical Sciences, and the University of Chicago Diabetes Research and Training Center.

More news from the University of Chicago: http://news.uchicago.edu/

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  1. kiersten

    this talks a lot about the axiety I finally came to understand this august and forgave and gave up on the hope that Karen said and you intimated that we would be able to be a family. I told her her how good it was too see the 4 of us together and that we were too old to change and I understood what she meant about lying to avoid confrontations (except for the confrontations she feels top dog on as you and Karen had put me on and artificial bottom for a long time when you spend no time looking into yourselves the way you need to. I went from every day if I didn’t come out of the room someone like roy coming in and asking me how I was feeling specifically emotionally or physically and if this was something that we should just mark down in the journal for the doctors, etc… And then when I’d be in too much pain to eat he’d bring me a toasted cheese, and I came here remembering all that stuff about how nothing was more important that family and when I got here, I got not only none of that but the opposite of that. I got that called a deficit. This little simple scientific experiment shows our simple animalistic fear behavior. As does our larger human behavior one. I just give thanks for all the people that made what you all did to me from the people I met here to some serious talks brought up NOT BY ME but by people on the mountains asking me alone with tutti either if Karen REALLY liked them because sometimes she sees so nice and other times she seems so cold and the EXACT same questions about you by 3 people with tutti standing there.

    You really need to watch

  2. kiersten

    this talks a lot about the axiety I finally came to understand this august and forgave and gave up on the hope that Karen said and you intimated that we would be able to be a family. I told her her how good it was too see the 4 of us together and that we were too old to change and I understood what she meant about lying to avoid confrontations (except for the confrontations she feels top dog on as you and Karen had put me on and artificial bottom for a long time when you spend no time looking into yourselves the way you need to. I went from every day if I didn’t come out of the room someone like roy coming in and asking me how I was feeling specifically emotionally or physically and if this was something that we should just mark down in the journal for the doctors, etc… And then when I’d be in too much pain to eat he’d bring me a toasted cheese, and I came here remembering all that stuff about how nothing was more important that family and when I got here, I got not only none of that but the opposite of that. I got that called a deficit. This little simple scientific experiment shows our simple animalistic fear behavior. As does our larger human behavior one. I just give thanks for all the people that made what you all did to me from the people I met here to some serious talks brought up NOT BY ME but by people on the mountains asking me alone with tutti either if Karen REALLY liked them because sometimes she sees so nice and other times she seems so cold and the EXACT same questions about you by 3 people with tutti standing there.

    You really need to watch no matter how much you hate tv and no matter how much I said to Karen and she agreed that we were all too old to change and have the family she used to say she could and I hope she really gets it not to lie to me to avoid confrontations like she does beth because being around liers just brings all thinking and energy down but as you will see there is a land breaking psychological view which also was part of changing my view and because you still don’t have the capacity to focus on researching for new research that will actually help me and since I have no problem getting off drugs again you are wasting your time trying to possibly sooth your ego which I’m only coming up with 2 easy criticisms that you can use when you see this video. You have to have one ready or seeing the video won’t be as life shocking. The funny thing is Roy and I read this book and were shocked and changed 7 years ago probably (mom refused to read anything that could help her by that time) but now they have make a spectacular free video which is the kinds of things that can not only free yourselves from the pain you all believe you can actually forget and not live in the past over when you never got over it in the first place but create yourself as a new wonderful person that doesn’t confuse people, who don’t have the understanding I finally do of it all… BTW don’t worry I don’t answer much to their questions but things like well what do you expect of someone who worked at the CIA or things like well dad and Karen are looking at big life changes which I’m sure is why someone asked why Karen seemed so nervous during your labor day party. As banal things as I can think of an if they want more I do then refer them to ask either you or her whoever is being asked about. where I’ll say that I also do not understand their different moods about different things and don’t feel comfortable specuating (unless I know) (ie. someones relative/dog just died, etc). New email for new link. ENjoy your vacation … Enjoy the video… I don’t know ANYONE who didn’t feel amazing after watching it and I already know you agree with some of the premise by understanding my prejudice against the under 16 year old Hispanics. Love, Kier

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