Not a request for advice, just help translating some information I got from the Angelman Syndrome Foundation, to which I donate on behalf of family members. They sent a breathless email today announcing a discovery in research on Angelman syndrome, and I can’t make much sense out of it. Can anybody help me understand this?
[QUOTE=Angelman Syndrome Foundation]
Today the Angelman Syndrome Foundation has very exciting news to share with you. In a research endeavor funded by the Angelman Syndrome Foundation, researchers at the University of North Carolina (UNC) have discovered the possible underlying cause of seizures in individuals with Angelman syndrome. <snip>
Using electrophysiological methods to record neuronal activity in mice with Angelman syndrome, the research team at UNC found defects in the neurotransmitter signals sent from inhibitory neurons to decrease activity in excitatory neurons. A balance between inhibitory and excitatory neurons is essential for proper neuron function, yet individuals with Angelman syndrome experience an imbalanced decrease in both neurons’ activities. However, this research discovered a disproportionately large decrease in inhibition compared to a smaller decrease in excitation, creating a hyper-excitable state that is believed to contribute to seizures in many individuals with Angelman syndrome. This fluctuating, improperly regulated brain activity might also underlie cognitive impairments in Angelman syndrome.
[/QUOTE]
I believe it is saying that there is a deficit in the neurons which would normally suppress other neurons which, unsuppressed, cause the intractable seizures (and possibly cognitive deficits) that occur in Angelman syndrome patients, but please correct me if I’m wrong. I can’t figure out what, if anything, this means for treatment of AS and/or the frequent seizures that are part of the disorder.
I have just a few questions and would be grateful for facts and thoughtful speculation.
[ul]
[li]Is there any indication that this is a significant breakthrough rather than just an attempt to say, “Here’s what your donation is paying for; please send more money?” The organization in question is very good about not soliciting for donations outside of the ones we normally make, so this email is unusual.[/li][li]Are there rays of hope in this discovery for treatment of existing Angelman patients or is this going to be more useful in preventing births of children with this disorder or detecting its potential in parents?[/li][li]I understand why overexcited neurons might be related to seizures, but how would the same neuronal activity relate to the cognitive dysfunction seen in people with AS?[/li][/ul]
This is an oversimplification, but neurons (brain cells) can act in two ways. They can make other neurons fire, which is called excitation, or they can stop other neurons from firing, which is called inhibition. A seizure is runaway excitatory activity. It starts in one spot of the brain, and can be transmitted like a fire all across the brain. The reason most people don’t have seizures is because the amounts of excitatory and inhibitory activity are balanced. If there’s a lot of activity in one region of the brain, inhibitory neurons will keep it from spreading over larger areas.
I’ve only read the press release, but to me it sounds like they’ve discovered that in Angelman’s Syndrome both excitatory and inhibitory neurons have a decreased amount of activity, but there’s a greater decrease in inhibitory neurons than in excitatory neurons. This means that even though overall activity is decreased, there’s a net excitatory effect, which is what’s causing the seizures. And as I discussed above, excitatory neurons need to be balanced with inhibitory neurons in order to prevent runaway brain activity.
This discovery sounds pretty cool to me (insert appropriate caveats here). They’ve found the mechanism that’s responsible for the disease, which is the first step before finding a treatment and a cure. Now they can look into what causes this decrease in activity, which is where the real fun begins.
For what it’s worth, there are some times in the lifespan, especially during early infancy, when humans are extremely susceptible to seizure activity. This is caused by changes in neurochemistry that result in an imbalance between excitatory and inhibitory activity. Thankfully, most of us grow out of it and are none the worse for wear. But seizures are scary no matter when they happen, and the more work done to figure out how to stop them the better.
The possibility for treatment or a cure depends on exactly what is causing the change in activity in the first place. If it’s due to changes in neurotransmitter levels, well, we can help with that. If it’s due to strict genetic factors, we can screen for that. But chances are that it’s going to be a very complicated combination of genetic and environmental factors that mess up during one very small and critical window in early development. That’s the way these things usually turn out, anyway.
As for what’s causing the decrease in cognitive function, they may have just found part of the answer. An overall decrease in the amount of neural activity could certainly effect cognitive capacity. That being said, we’re still trying to figure out how human cognition works, so it’s hard to give any straight answers. If I were to hazard a guess, I would say that a small change during prenatal development causes a “hiccup” when the brain is forming and getting wired up. This developmental hiccup means that the overall amount of neural activity is decreased, and this could be caused by a decrease in the number of neurons, a decrease in the number of connections between neurons, an increase in the time it takes neurons to signal each other, a decrease in the amount of certain neurotransmitters, or a combination of all of the above. But this decrease in activity limits the amount of things you can do with your brain at any given time. Some brain functions are absolutely necessary (controlling breathing, heartbeat, body temperature, and so on), while others are less necessary (playing a game of mental 3D chess), so you can guess which functions take the hit.
But, this does sounds like exciting news for the Angelman Syndrome Foundation, and I congratulate them on funding this discovery.
Oh, and on behalf of all the research scientists out there who are desperate for funding, thank you so much for contributing to research!
Thank you so much! That was a very understandable and comprehensive answer and I greatly appreciate the time you put into your response. Your enthusiasm for this discovery (understanding the caveat) is very encouraging, so I’ll allow myself to feel just a bit gleeful and hopeful. I do understand that there is no magic wand that will remove the challenge of this disorder from our family’s little turnip, but it sounds like this information could definitely contribute to a successful treatment for her seizures, which are terrifying and relentless and increasingly frequent despite medication.
Could this net surplus of activity in the neurons also relate to the physical hyperactivity seen in Angelman’s kids? My relative, who is still a preschooler, is in constant motion—and faster than a speeding bullet when you set down a cup of coffee on the end table! From what I’ve read, this hyperactivity usually decreases as the child ages but the seizures don’t, so I suppose I could be just conflating two completely unrelated meanings for “overactive.” Regardless, I’m relieved and excited that they are making progress and comforted that people like you are out studying how our brains work and what can make them work better.
As far as the donations go, it’s the least we can do. As I’m sure you know, the more uncommon disorders like Angelman syndrome don’t get a lot of ribbons and walks and TV news reports, so we try to give whatever we can to them. I think from now on they’ll get the egg money, too :D.
Yeah, I think at this point that a link between the discovery and overactivity is tenuous at best. A seizure is a relatively simple thing to understand, as neuroscience goes. It’s a short-term, temporary phenomenon with a clear cause. Hyperactivity involves a lot of different behaviors, across a much larger section of the brain, for a much longer time span. That’s not to say that there’s not a link, but the two things are very different, and I think we just don’t understand the brain well enough yet to make that kind of determination.
You’re quite welcome! I’m always happy to try to explain the brain to the masses.
As far as the hyperactivity goes, it’s hard to say what could be causing it. But, I would speculate that the developmental hiccup that caused the changes in brain activity also altered other body systems that were developing at the same time. The big thing to remember is that in the body nothing happens in isolation, and that goes double for during development. Everything is connected, and a small change in one part of the body, like the brain, can have huge, unpredictable ramifications for other body systems, like digestion, bone formation, or even the amount and distribution of hormones like adrenaline.
So, what you see in Angelman’s Syndrome are symptoms that all reflect an underlying change in body organization, and the big question is “what’s the ultimate cause of all these changes.” There’s definitely more work to be done, but the scientists have a good starting point, and sometimes that’s all you need to make a breakthrough discovery.
That makes sense, especially when I visualize the type of activity she engages in. She is always wiggling and grasping and rocking and tapping her feet, but there is a sense of direction and intention to it, while the seizures are typical grand mal events which are obviously not being controlled by her on any conscious level.
Well, you do a great job of it, and I am grateful to both you and Smeghead. I feel better prepared now to talk to the child’s parents about this research finding without sounding like a total neuronoob :D.
Gosh. I’m going to sound awful here but I have to say it. That breathless e-mail strikes me more as an emerging awareness that some donors may send their money elsewhere without feeling that their donations are bearing some fruit.
Angelman Syndrome (AS) is a fascinating disease but there is not much breakthrough in that announcement. The genes and locii associate with (AS) are well identified. It occurs when there is genomic imprinting leading to reduction of a maternally derived gene for ubiquitin protein ligase. Similar defects of the paternally derived gene lead to a different disorder: Prader-Wili. The full syndrome with the difficult to control seizures also requires nearby genes to be effected as well including but not limited to some GAGA receptor subunit genes (GABA neurons are considered inhibitory). The e-mail seems to refer some work that identified how, in a mouse model, a particular subpopulation of neurons, interneurons, seems to be differentially effected by the ubiquitin protein ligase deficiency, and how that may lead to the known imbalance of less excitatory decrease than inhibitory decrease. Very interesting but not “breakthrough.”
Before you give the egg money you should also realize that the odds of any of this basic science helping your family member is very remote. It is likely not even going to particularly help others with AS in the future, or at least no more so than it will help those with other seizure disorders, autistic disorders, and a host of other brain, including perhaps some psychiatric, problems. The benefit is indeed more basic: by understanding how AS occurs the researchers discover basic principles of brain physiology and those developments help in a much broader sense.
Good stuff. Not breakthrough though. Good cause to give to even if your family member never sees the benefit. And good explanation by Della of inhibitory and excitatory neurons and how problems at one point in development distort how the brain develops and works in the future even if the defect itself magically disappeared at a later date.