Neuroscience
Month
The same sex hormone that helps protect females from stroke may also reduce their risk of autism, scientists say.
In the first look at a potential role of the female sex hormone in autism, researchers at the Medical College of Georgia at Georgia Regents University have found expression of estrogen receptor beta – which enables estrogen’s potent brain protection – is significantly decreased in autistic brains. The receptor also plays a role in locomotion as well as behavior, including anxiety, depression, memory, and learning.
"If you ask any psychiatrist seeing patients with autistic behavior their most striking observation from the clinic, they will say there are more males compared to females," said Dr. Anilkumar Pillai, MCG neuroscientist and corresponding author of the study in Molecular Autism.
Estrogen is known to help protect premenopausal women from maladies such as stroke and impaired cognition. Exposure to high levels of the male hormone testosterone during early development has been linked to autism, which is five times more common in males than females.
The new findings of reduced expression of estrogen receptor beta as well as that of an enzyme that converts testosterone to estrogen could help explain the high testosterone levels in autistic individuals and higher autism rates in males, Pillai said.
It was the 5-to-1 male-to-female ratio along with the testosterone hypothesis that led Pillai and his colleagues to pursue whether estrogen might help explain the significant gender disparity and possibly point toward a new treatment.
"The testosterone hypothesis is already there, but nobody had investigated whether it had anything to do with the female hormone in the brain," Pillai said. "Estrogen is known to be neuroprotective, but nobody has looked at whether its function is impaired in the brain of individuals with autism. We found that the children with autism didn’t have sufficient estrogen receptor beta expression to mediate the protective benefits of estrogen."
Comparing the brains of 13 children with and 13 children without autism spectrum disorder, the researchers found a 35 percent decrease in estrogen receptor beta expression as well as a 38 percent reduction in the amount of aromatase, the enzyme that converts testosterone to estrogen.
Levels of estrogen receptor beta proteins, the active molecules that result from gene expression and enable functions like brain protection, were similarly low. There was no discernable change in expression levels of estrogen receptor alpha, which mediates sexual behavior.
The study focused on the brain’s prefrontal cortex, which is involved in social behavior and cognition. Brain tissue from both autistic and healthy subjects was obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland. The children died at an average age of 11 from drowning, other accidents, or suicide. All the brain tissue was from male children except for one control.
While much work remains, estrogen receptor beta agonists, which are already known to improve brain plasticity and memory in animals, might one day help reverse autism’s behavioral deficits, such as reclusiveness and repetitive behavior, Pillai said.
The scientists already are moving to animal studies to see what happens when they reduce estrogen receptor beta expression in mice. They also plan to give an estrogen receptor beta agonist – which should increase receptor function – to a mouse with generalized inflammation and signs of autism to see if it mitigates those signs. Inflammation is a factor in many diseases of the brain and body, and estrogen receptor beta agonists already are in clinical trials for schizophrenia
Larger, follow-up studies should also include comparing expression of testosterone receptor levels in healthy and autistic children, Pillai said. MCG scientists also want to know more about why the reduced beta receptor expression occurs.
Studies published in the journal Molecular Psychiatry earlier this year by scientists at the University of Cambridge and Denmark’s Statens Serum Institute showed that male children who develop autism were exposed to higher levels of steroid hormones, including testosterone and progesterone, during development than their healthy peers.
The incidence of autism has increased about 30 percent in the past two years in the United States, to the current rate of about 1 in 68 children, according to the Centers for Disease Control and Prevention. Most children are diagnosed at about age 4, although the disorder can be diagnosed by about age 2, according to the CDC. Diagnosis is made through extensive behavioral and psychological testing.
A type of lipid that naturally declines in the aging brain impacts – within laboratory models used to study Parkinson’s disease – a protein associated with the disease, according to a study co-authored by University of Alabama researchers.
The study, which published today in the Proceedings of the National Academy of Sciences, focuses on lipids, fat-like molecules that naturally occur in organisms, and their potential roles in a complex process that leads to the death of neurons that produce dopamine. When dopamine-producing neurons malfunction or die, this leads to the symptoms associated with Parkinson’s disease.
“This gets right to the heart of understanding, possibly, the mechanism by which one form of lipid is impacting the process of neuron degeneration,” said Dr. Guy Caldwell, UA professor of biological sciences and one of the study’s co-authors.
The study, led by researchers at the Louisiana State University Health Sciences Center, focused on phosphatidylethanolamine, a lipid known as PE. Today’s scholarly article details how low levels of PE lead to high-levels of alpha-synuclein, a protein previously linked to Parkinson’s. It also show the promise a second lipid, ethanolamine, or ETA, has in boosting PE levels.
To function correctly, proteins must fold properly within cells. One misfolding, as can occur when extra copies of the protein alpha-synuclein are present, can lead to others and, subsequently, to aggregation, or clumping, of proteins. Aggregation of proteins can lead to neuron malfunction or cell death.
Previous research had shown that excess alpha-synuclein can serve as an intra-cellular “roadblock,” preventing proteins, dopamine and other things cells need from being delivered to their necessary locations. This delivery disruption can lead to serious disorders.
“That situation is being applied here, but in a different way,” Caldwell said. “We’re gaining a better understanding of the importance these lipids, which are components of cellular membranes, have in maintaining proper trafficking.”
A proper link with alpha-synuclein helps “lipid rafts” in their transport of proteins.
“As the name implies, lipid rafts are like rafts of fat,” Caldwell said. “If alpha-synuclein can’t associate with those rafts, it could be a toxic situation for these cells.”
Using yeast and the tiny nematode C. elegans as laboratory models, the researchers showed they could reverse the delivery problem by adding ETA to the mix.
“This supplementation of ETA basically tells us that if we can restore the amount of PE that is being made, we can create a healthier situation in neurons, and this might help them to survive longer.”
UA’s lead author on the study is Siyuan “Alice” Zhang, a third-year UA doctoral student who works in the Caldwell lab. Dr. Kim Caldwell, UA professor of biological sciences, is also a co-author. LSU’s senior researcher on the project is Dr. Stephan Witt.
Additional study is needed in rodents and patient-derived stem cells before knowing how beneficial the discovery could eventually prove, Caldwell said.
Perhaps one day, Caldwell said, a supplement could be developed to prevent the decline of PE or possibly a drug could be developed to activate an enzyme that converts ETA to PE.
“I think it has promise as a new way of looking at alleviating toxicity,” Caldwell said. “It’s a different angle.”
People can become addicted to eating for its own sake but not to consuming specific foods such as those high in sugar or fat, research suggests.
An international team of scientists has found no strong evidence for people being addicted to the chemical substances in certain foods.
The brain does not respond to nutrients in the same way as it does to addictive drugs such as heroin or cocaine, the researchers say.
Instead, people can develop a psychological compulsion to eat, driven by the positive feelings that the brain associates with eating.
"This is a behavioural disorder and could be categorised alongside conditions such as gambling addiction", say scientists at Edinburgh.
They add that the focus on tackling the problem of obesity should be moved from food itself towards the individual’s relationship with eating.
The study, which examined the scientific evidence for food addiction as a substance-based addiction, is published in Neuroscience & Biobehavioral Reviews.
The researchers also say that the current classification of mental disorders, which does not permit a formal diagnosis of eating addiction, could be redrawn.
However, more research would be needed to define a diagnosis, the scientists add.
They add that the focus on tackling the problem of obesity should be moved from food itself towards the individual’s relationship with eating.
Feeling socially disconnected may lead us to lower our threshold for determining that another being is animate or alive, according to new research published in Psychological Science, a journal of the Association for Psychological Science.
“This increased sensitivity to animacy suggests that people are casting a wide net when looking for people they can possibly relate to — which may ultimately help them maximize opportunities to renew social connections,” explains psychological scientist and lead researcher Katherine Powers of Dartmouth College.
These findings enhance our understanding of the factors that contribute to face perception, mind perception, and social relationships, but they could also shed light on newer types of relationships that have emerged in the modern age, Powers argues, including our relationships with pets, online avatars, and even pieces of technology, such as computers, robots, and cell phones.
Feeling socially connected is a critical part of human life that impacts both mental and physical health; when we feel disconnected from others, we try to replenish our social connections.
“As social beings, we have an intrinsic motivation to pay attention to and connect with other people,” says Powers. “We wanted to examine the influence of this social motive on one of the most basic, low-level aspects of social perception: deciding whether or not a face is alive.”
Powers and colleagues had 30 college students view images of faces, which were actually morphs created by combining inanimate faces (such as a doll’s face) with human faces. The morphs ranged from 0% human to 100% human and showed both male and female faces.
The morphs were presented in random order and the students had to decide whether each face was animate or inanimate. Afterwards, they completed a survey that gauged their desire for social connections, in which they rated their agreement with statements such as “I want other people to accept me.”
The data revealed that desire for social connections was associated with a lower threshold for animacy. In other words, participants who had high scores on the social connections measure didn’t need to see as many human-like features in a face order to decide that it was alive.
To see if there might be a causal link, Powers and colleagues conducted another study in which they experimentally manipulated feelings of social connection.
A separate group of college students completed a personality questionnaire and were provided feedback ostensibly based on the questionnaire. In reality, the feedback was determined by random assignment. Some students were told that their future lives would be isolated and lonely, while others were told their lives would contain long-lasting, stable relationships. The feedback also included personality descriptions and statements tailored to each participant to ensure believability.
The students then viewed the face morphs.
As expected, students who had been told they would be isolated and lonely showed lower thresholds for animacy than those who were told they would have long-lasting relationships.
These findings are particularly interesting, the researchers argue, because previous research has shown that people are typically cautious in determining whether a face is alive:
“What’s really interesting here is the degree of variability in this perception,” says Powers. “Even though two people may be looking at the same face, the point at which they see life and decide that person is worthy of meaningful social interaction may not be the same — our findings show that it depends on an individual’s social relationship status and motivations for future social interactions.”
“I think the fact that we can observe such a bias in the perception of basic social cues really underscores the fundamental nature of the human need for social connection,” Powers adds.
An international team of researchers has identified a new inherited neuromuscular disorder. The rare condition is the result of a genetic mutation that interferes with the communication between nerves and muscles, resulting in impaired muscle control.
The new disease was diagnosed in two families – one in the U.S. and the other in Great Britain – and afflicts multiple generations. The discovery was published in the American Journal of Human Genetics.
“This discovery gives us new insight into the mechanisms of diseases that are caused by a breakdown in neuromuscular signal transmission,” said David Herrmann, M.B.B.Ch., a professor in the Department of Neurology at the University of Rochester School of Medicine and Dentistry and co-lead author of the study. “It is our hope that these findings will help identify new targets for therapies that can eventually be used to treat these diseases.”
The focus of the research is the neuromuscular junction, the point at which the axon fibers that extend from peripheral nerves meet the muscle cells. The chemical signals that pass across the junction are essential for motor function.
There are a number of disorders – both acquired and inherited – that interfere with the communication that occurs at the neuromuscular junction. For example, in Lambert-Eaton myasthenic syndrome, which is most commonly triggered by certain cancers, the body’s own immune system attacks the neuromuscular junction, interrupting signal transmission. These diseases, which are rare, result in muscle weakness and fatigue, primarily in the limbs.
While the families in the study had at one point been diagnosed with other neuromuscular conditions, the researchers identified them as unique, due to their particular motor abnormalities, including problems resembling Lambert-Eaton, and because the disease was passed from one generation to the next.
The researchers compiled a genetic profile of the family members. Specifically, they analyzed the section of DNA code responsible for creating proteins using a technique called whole exome sequencing.
They discovered that the two different families had mutations in the code that creates the protein synaptotagmin 2 (SYT2). Scientists have long understood the function of this protein, but it had never before been associated with a disease in humans.
SYT2 is present at the pre-synaptic terminal, the end of the nerve cell that sits at the neuromuscular junction and helps the cells sense fluctuations in calcium levels. Calcium plays an important role in the electrical function of cells and, in the case of the neuromuscular junction, helps dictate the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells.
In the two families, the mutation disrupted the ability of the nerve cells to sense the changes in calcium levels that would normally trigger the release of acetylcholine. As a result, communication was disrupted and muscle control was impaired.
The authors have used the mutation in SYT2 to create a fruit fly (drosophila) model of the disease. Fruit flies are an important research tool and the study of their neurobiology has contributed greatly to our understanding of neurological development and diseases and the researchers see this as a first step to the development of potential new therapies to treat the condition.
What’s the price on your integrity? Tell the truth; everyone has a tipping point. We all want to be honest, but at some point, we’ll lie if the benefit is great enough. Now, scientists have confirmed the area of the brain in which we make that decision.
The result was published online this week in Nature Neuroscience.
Nerves and blood vessels lead intimately entwined lives. They grow up together, following similar cues as they spread throughout the body. Blood vessels supply nerves with oxygen and nutrients, while nerves control blood vessel dilation and heart rate.
Neurovascular relationships are especially important in the brain. Studies have shown that when neurons work hard, blood flow increases to keep them nourished. Scientists have been asking whether neural activity also changes the structure of local vascular networks.
According to new research published in the Sept. 3 issue of Neuron, the answer is yes.
Creating induced pluripotent stem cells or iPS cells allows researchers to establish “disease in a dish” models of conditions ranging from Alzheimer’s disease to diabetes. Scientists at Yerkes National Primate Research Center, Emory University have now applied the technology to a model of Huntington’s disease (HD) in transgenic nonhuman primates, allowing them to conveniently assess the efficacy of potential therapies on neuronal cells in the laboratory.
(Image caption: Neural progenitor cells derived from transgenic rhesus macaque iPS cells show features of Huntington’s disease pathology, making them a useful tool for therapeutic discovery.)
The results were published this week in Stem Cell Reports.
"A highlight of our model is that our progenitor cells and neurons developed cellular features of HD such as intranuclear inclusions of mutant Huntingtin protein, which most of the currently available cell models do not present," says senior author Anthony Chan, PhD, DVM, associate professor of human genetics at Emory University School of Medicine and Yerkes National Primate Research Center. "We could use these features as a readout for therapy using drugs or a genetic manipulation."
Chan and his colleagues were the first in the world to establish a transgenic nonhuman primate model of HD. HD is an inherited neurodegenerative disorder that leads to the appearance of uncontrolled movements and cognitive impairments, usually in adulthood. It is caused by a mutation that introduces an expanded region where one amino acid (glutamine) is repeated dozens of times in the huntingtin protein.
The non-human primate model has extra copies of the huntingtin gene that contains the expanded glutamine repeats. In the non-human primate model, motor and cognitive deficits appear more quickly than in most cases of Huntington’s disease in humans, becoming noticeable within the first two years of the monkeys’ development.
First author Richard Carter, PhD, a graduate of Emory’s Genetics and Molecular Biology doctoral program, and his colleagues created iPS cells from the transgenic monkeys by reprogramming cells derived from the skin or dental pulp. This technique uses retroviruses to introduce reprogramming factors into somatic cells and induces a fraction of them to become pluripotent stem cells. Pluripotent stem cells are able to differentiate into any type of cell in the body, under the right conditions.
Carter and colleagues induced the iPS cells to become neural progenitor cells and then differentiated neurons. The iPS-derived neural cells developed intracellular and intranuclear aggregates of the mutant huntingtin protein, a classic sign of Huntington’s pathology, as well as an increased sensitivity to oxidative stress.
The sensitivity to oxidative stress was a useful indicator; it could be ameliorated in cell culture, either by a RNA-based gene knockdown approach, or the drug memantine, which is currently being investigated for Huntington’s disease in a human clinical trial.
"We tested two known experimental interventions, but our findings are a proof of principle that this system could be a valuable tool for the discovery and evaluation of other therapies," Chan says.
Despite the barrage of visual information the brain receives, it retains a remarkable ability to focus on important and relevant items. This fall, for example, NFL quarterbacks will be rewarded handsomely for how well they can focus their attention on color and motion – being able to quickly judge the jersey colors of teammates and opponents and where they’re headed is a valuable skill. How the brain accomplishes this feat, however, has been poorly understood.
Now, University of Chicago scientists have identified a brain region that appears central to perceiving the combination of color and motion. They discovered a unique population of neurons that shift in sensitivity toward different colors and directions depending on what is being attended – the red jersey of a receiver headed toward an end zone, for example. The study, published Sept. 4 in the journal Neuron, sheds light on a fundamental neurological process that is a key step in the biology of attention.
“Most of the objects in any given visual scene are not that important, so how does the brain select or attend to important ones?” said study senior author David Freedman, PhD, associate professor of neurobiology at the University of Chicago. “We’ve zeroed in on an area of the brain that appears central to this process. It does this in a very flexible way, changing moment by moment depending on what is being looked for.”
The visual cortex of the brain possesses multiple, interconnected regions that are responsible for processing different aspects of the raw visual signal gathered by the eyes. Basic information on motion and color are known to route through two such regions, but how the brain combines these streams into something usable for decision-making or other higher-order processes remained unclear.
To investigate this process, Freedman and postdoctoral fellow Guilhem Ibos, PhD, studied the response of individual neurons during a simple task. Monkeys were shown a rapid series of visual images. An initial image showed either a group of red dots moving upwards or yellow dots moving downwards, which served as an instruction for which specific colors and directions were relevant during that trial. The subjects were rewarded when they released a lever when this image later reappeared. Subsequent images were composed of different colors of dots moving in different directions, among which was the initial image.
Dynamic neurons
Freedman and Ibos looked at neurons in the lateral intraparietal area (LIP), a region highly interconnected with brain areas involved in vision, motor control and cognitive functions. As subjects performed the task and looked for a specific combination of color and motion, LIP neurons became highly active. They did not respond, however, when the subjects passively viewed the same images without an accompanying task.
When the team further investigated the responses of LIP neurons, they discovered that the neurons possessed a unique characteristic. Individual neurons shifted their sensitivity to color and direction toward the relevant color and motion features for that trial. When the subject looked for red dots moving upwards, for example, a neuron would respond strongly to directions close to upward motion and to colors close to red. If the task was switched to another color and direction seconds later, that same neuron would be more responsive to the new combination.
“Shifts in feature tuning had been postulated a long time ago by theoretical studies,” Ibos said. “This is the first time that neurons in the brain have been shown to shift their selectivity depending on which features are relevant to solve a task.”
Freedman and Ibos developed a model for how the LIP brings together both basic color and motion information. Attention likely affects that process through signals from higher-order areas of the brain that affect LIP neuron selectivity. The team believes that this region plays an important role in making sense of basic sensory information, and they are trying to better understand the brain-wide neuronal circuitry involved in this process.
“Our study suggests that this area of the brain brings together information from multiple areas throughout the brain,” Freedman said. “It integrates inputs – visual, motor, cognitive inputs related to memory and decision making – and represents them in a way that helps solve the task at hand.”
Paula Meltzer was only 38 when out of nowhere everything she looked at was blurry. For the single mother, who had a lucrative career as a gemologist and spent hours examining valuable pieces of jewelry, it seemed as if – in a split second – her life changed.
At first doctors thought Meltzer had a brain tumor. What they determined after further tests, however, was that she had multiple sclerosis, an autoimmune disease that affects the brain and central nervous system and was causing optic neuritis, an inflammation of the optic nerve that can cause a partial or complete loss of vision.
“I was living independently, doing my job, taking care of my child – and then I had to look to my parents to take care of me,” Meltzer said.
Almost two decades later, Meltzer, out of a wheelchair and walking without a cane, was one of 14 women with moderate disability due to MS who participated in a pilot trial conducted by the Rutgers School of Health Related Professions. A specially-designed yoga program for these MS patients not only improved their physical and mental well-being but also enhanced their overall quality of life.
“I felt like I became steadier and stronger in my core,” Meltzer said. Prior to yoga, she described herself as a “wall walker,” someone who felt safer holding onto the wall in order to get around. “To be able to stand on one leg and feel balanced is amazing.”
Susan Gould Fogerite, director of research for the Institute for Complementary and Alternative Medicine in the School of Health Related Professions, said that although there is widespread evidence that yoga is being used as a form of exercise by those with MS, much of the feedback has been anecdotal and there isn’t much empirical data regarding its safety and efficacy.
This is why she and her colleagues, Evan Cohen and David Kietrys, physical therapists and associate professors in the School of Health Related Professions at Stratford, decided to undertake the small pilot study, believing that a specialized yoga program for MS patients – which incorporates mind, body and spirit – would be beneficial to everyday living.
What they discovered at the end of the eight-week trial was that those who participated were better able to walk for short distances and longer periods of time, had better balance while reaching backwards, fine motor coordination, and were better able to go from sitting to standing. Their quality of life also improved in perceived mental health, concentration, bladder control, walking, and vision, with a decrease in pain and fatigue.
“Yoga is not just exercise, it is a whole system of living,” said Fogerite, an associate professor, who, along with Kietrys, will present the results on September 26 at the Symposium on Yoga Research at the Kripalu Institute in Massachusetts. “The panel of experts who advised us on the trial wanted to make sure that we provided a fully integrated program that included philosophy, breathing practices, postures, relaxation and meditation.”
The yoga pilot trial was held at Still Point Yoga Center in Laurel Springs, a southern New Jersey town close to Philadelphia. Of the 72 individuals who were interested in participating, only 16 were eligible based on medical and other criteria and availability. Of those, 15 were enrolled and 14 completed the program after one person had to withdraw because of an unrelated health problem.
Meltzer and the other women who participated in the trial ranged in age from 34 to 64. Some had been diagnosed with MS within the last two years while others had been living with the illness for up to 26 years. For 90 minutes, twice a week for two months, they practiced techniques and exercises that would improve their posture, help to increase stamina, and teach them how to relax and focus.
“This study, I hope, is one of many that will give us the clinical information we need,” said Fogerite. “Yoga is not currently being widely prescribed for people with MS, although it might turn out to be a very helpful treatment.”
The yoga practices were done by the women in the study sitting, standing, or lying on yoga mats, and using metal folding chairs situated close to the wall to provide them with more support.
“What was so nice about this experience was that although everyone was at a different level of the disease, we felt like we were all together, so I think the camaraderie helped,” said Meltzer. “And it wasn’t just about gaining more mobility and balance in our legs but our arms and necks felt stronger as well.”
Fogerite said a larger randomized controlled trial would be needed to determine whether yoga could be used as a prescribed treatment for individuals with moderate disability due to MS. More than 2.3 million people – two to three times more women than men – throughout the world are diagnosed with this disease which can cause poor coordination, loss of balance, slurred speech, tremors, numbness, extreme fatigue and problems with memory and concentration.
“When I was first diagnosed I no longer felt safe in my own body,” Meltzer said. “I didn’t trust my body at all. What the program did was really bring that trust back.”
Sleep difficulties may be linked to faster rates of decline in brain volume, according to a study published in the September 3, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Sleep has been proposed to be “the brain’s housekeeper”, serving to repair and restore the brain.
The study included 147 adults 20 and 84 years old. Researchers examined the link between sleep difficulties, such as having trouble falling asleep or staying asleep at night, and brain volume.
All participants underwent two MRI brain scans, an average of 3.5 years apart, before completing a questionnaire about their sleep habits.
A total of 35 percent of the participants met the criteria for poor sleep quality, scoring an average of 8.5 out of 21 points on the sleep assessment. The assessment looked at how long people slept, how long it took them to fall asleep at night, use of sleeping medications, and other factors.
The study found that sleep difficulties were linked with a more rapid decline in brain volume over the course of the study in widespread brain regions, including within frontal, temporal and parietal areas.
The results were more pronounced in people over 60 years old.
“It is not yet known whether poor sleep quality is a cause or consequence of changes in brain structure,” said study author Claire E. Sexton, DPhil, with the University of Oxford in the United Kingdom. “There are effective treatments for sleep problems, so future research needs to test whether improving people’s quality of sleep could slow the rate of brain volume loss. If that is the case, improving people’s sleep habits could be an important way to improve brain health.”
A gene crucial for brain and heart development may also be associated with sudden unexplained death in epilepsy (SUDEP), the most common cause of early mortality in epilepsy patients.
Scientists at The University of Texas MD Anderson Cancer Center have created a new animal model for SUDEP and have shown that mice who have a partial deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) are more likely to develop spontaneous seizures and sudden death. The finding occurred when observing mice originally bred for studying a link between SENP2 deficiency and cancer.
"SENP2 is highly present in the hippocampus, a critical brain region for seizure genesis," said Edward Yeh, M.D., chair of cardiology at MD Anderson. "Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population, with SUDEP the most common epilepsy-related cause of death."
Yeh’s findings were published in this month’s issue of Neuron.
Although it’s not yet known what causes SUDEP in humans, inactivation of potassium channels genes have been linked to SUDEP in animal models. Potassium channels are found in most cell types and control a large variety of cell functions.
"These animal models demonstrated an important connection between the brain and heart. However, it remains unclear whether seizure and sudden death are two separate manifestations of potassium channel deficiency in the brain and the heart, or whether seizures predispose the heart to lethal cardiac arrhythmia," said Yeh.
The study revealed that when SENP2 was deficient in the brain, seizures activated a part of the nervous system responsible for regulating the heart’s electrical system. This resulted in a phenomenon known as atrioventricular conduction block, which effectively slowed down and then stopped the heart.
Yeh’s team observed that the SENP2-deficient mice appeared normal at birth, but by 6 to 8 weeks, experienced convulsive seizures, and then sudden death. He believes the reason may lie with protein modifiers called SUMO. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.
"One of the channels, Kv7, is significantly diminished or ‘closed’ due to the lack of SENP2," said Yeh. "In mice this led to seizures and cardiac arrest."
In humans, the good news is that an FDA-approved drug, retigabine works by “opening” the Kv7 channel. The therapy was developed for treating partial-onset seizures. The findings in Yeh’s new mouse model clearly demonstrate a previously unknown cause of SUDEP, which may open up new opportunities for study and treatment in the future.