Posts tagged neuroscience
Articles and news from the latest research reports.
Analysis of 26 networked autism genes suggests functional role in the cerebellum
A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.
The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied.
The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.
Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.
Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation.
Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.
Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe.
The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.
“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.
Certain blood pressure drugs slow dementia deterioration
A class of drug, called ACE inhibitors, which are used to lower blood pressure, slow the rate of cognitive decline typical of dementia, suggests research published in the online journal BMJ Open.
Furthermore, these drugs may even boost brain power, the research indicates.
The researchers compared the rates of cognitive decline in 361 patients who had either been diagnosed with Alzheimer’s disease, vascular dementia, or a mix of both.
Eighty five of the patients were already taking ACE inhibitors; the rest were not.
The researchers also assessed the impact of ACE inhibitors on the brain power of 30 patients newly prescribed these drugs, during their first six months of treatment. The average age of all the participants was 77.
Between 1999 and 2010, the cognitive decline of each patient was assessed using either the Standardised Mini Mental State Examination (SMMSE) or the Quick Mild Cognitive Impairment (Qmci) screen on two separate occasions, six months apart.
Compared with those not taking ACE inhibitors, those on these drugs experienced marginally slower rates of cognitive decline.
In those whose brain power had been assessed by Qmci, which is a more sensitive screen than the SMMSE, the difference was small, but significant.
And the brain power of those patients newly prescribed ACE inhibitors actually improved over the six month period, compared with those already taking them, and those not taking them at all.
This might be because these patients stuck to their medication regimen better, or it might be a by-product of better blood pressure control, or improved blood flow to the brain, suggest the authors.
But it is the first time that there has been any evidence to suggest that blood pressure lowering drugs may not only halt cognitive decline, but may actually improve brain power.
“This [study] supports the growing body of evidence for the use of ACE inhibitors and other [blood pressure lowering] agents in the management of dementia,” write the authors.
“Although the differences were small and of uncertain clinical significance, if sustained over years, the compounding effects may well have significant clinical benefits,” they add.
They caution, however, that recent evidence indicates that ACE inhibitors may be harmful in some cases, so if larger studies confirm that they work well in dementia, it may be only certain groups of patients with the condition who stand to benefit.
(Source: group.bmj.com)
Scientists ID compounds that target amyloid fibrils in Alzheimer’s, other brain diseases
UCLA chemists and molecular biologists have for the first time used a “structure-based” approach to drug design to identify compounds with the potential to delay or treat Alzheimer’s disease, and possibly Parkinson’s, Lou Gehrig’s disease and other degenerative disorders.
All of these diseases are marked by harmful, elongated, rope-like structures known as amyloid fibrils, linked protein molecules that form in the brains of patients.
Structure-based drug design, in which the physical structure of a targeted protein is used to help identify compounds that will interact with it, has already been used to generate therapeutic agents for a number of infectious and metabolic diseases.
The UCLA researchers, led by David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator, report the first application of this technique in the search for molecular compounds that bind to and inhibit the activity of the amyloid-beta protein responsible for forming dangerous plaques in the brain of patients with Alzheimer’s and other degenerative diseases.
In addition to Eisenberg, who is also a professor of chemistry, biochemistry and biological chemistry and a member of UCLA’s California NanoSystems Institute, the team included lead author Lin Jiang, a UCLA postdoctoral scholar in Eisenberg’s laboratory and Howard Hughes Medical Institute researcher, and other UCLA faculty.
The research was published July 16 in eLife, a new open-access science journal backed by the Howard Hughes Medical Institute, the Max Planck Society and the Wellcome Trust.
A number of non-structure-based screening attempts have been made to identify natural and synthetic compounds that might prevent the aggregation and toxicity of amyloid fibrils. Such studies have revealed that polyphenols, naturally occurring compounds found in green tea and in the spice turmeric, can inhibit the formation of amyloid fibrils. In addition, several dyes have been found to reduce amyloid’s toxic effects, although significant side effects prevent them from being used as drugs.
Armed with a precise knowledge of the atomic structure of the amyloid-beta protein, Jiang, Eisenberg and colleagues conducted a computational screening of 18,000 compounds in search of those most likely to bind tightly and effectively to the protein.
Those compounds that showed the strongest potential for binding were then tested for their efficacy in blocking the aggregation of amyloid-beta and for their ability to protect mammalian cells grown in culture from the protein’s toxic effects, which in the past has proved very difficult. Ultimately, the researchers identified eight compounds and three compound derivatives that had a significant effect.
While these compounds did not reduce the amount of protein aggregates, they were found to reduce the protein’s toxicity and to increase the stability of amyloid fibrils — a finding that lends further evidence to the theory that smaller assemblies of amyloid-beta known as oligomers, and not the fibrils themselves, are the toxic agents responsible for Alzheimer’s symptoms.
The researchers hypothesize that by binding snugly to the protein, the compounds they identified may be preventing these smaller oligomers from breaking free of the amyloid-beta fibrils, thus keeping toxicity in check.
An estimated 5 million patients in the U.S. suffer from Alzheimer’s disease, the most common form of dementia. Alzheimer’s health care costs in have been estimated at $178 billion per year, including the value of unpaid care for patients provided by nearly 10 million family members and friends.
In addition to uncovering compounds with therapeutic potential for Alzheimer’s disease, this research presents a new approach for identifying proteins that bind to amyloid fibrils — an approach that could have broad applications for treating many diseases.
Many experts believe that chronic fatigue syndrome (CFS) has several root causes including some viruses. Now, lead scientists Shara Pantry, Maria Medveczky and Peter Medveczky of the University of South Florida’s Morsani College of Medicine, along with the help of several collaborating scientists and clinicians, have published an article in the Journal of Medical Virology suggesting that a common virus, Human Herpesvirus 6 (HHV-6), is the possible cause of some CFS cases.
Over 95 percent of the population is infected with HHV-6 by age 3, but in those with normal immune systems the virus remains inactive. HHV-6 causes fever and rash (or roseola) in infants during early childhood, and is spread by saliva. In immunocompromised patients, it can reactivate to cause neurological dysfunction, encephalitis, pneumonia and organ failure.
“The good news reported in our study is that antiviral drugs improve the severe neurological symptoms, including chronic pain and long-term fatigue, suffered by a certain group of patients with CFS,” said Medveczky, who is a professor of molecular medicine at USF Health and the study’s principal investigator. “An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from the application of this research including antiviral drug therapy.”
The link between HHV-6 infection and CFS is quite complex. After the first encounter, or “primary infection,” all nine known human herpesviruses become silent, or “latent,” but may reactivate and cause diseases upon immunosuppression or during aging. A previous study from the Medveczky laboratory showed that HHV-6 is unique among human herpesviruses; during latency, its DNA integrates into the structures at the end of chromosomes known as telomeres.
Furthermore, this integrated HHV-6 genome can be inherited from parent to child, a condition commonly referred to as “chromosomally integrated HHV-6,” or CIHHV-6. By contrast, the “latent” genome of all other human herpesviruses converts to a circular form in the nucleus of the cell, not integrated into the chromosomes, and not inheritable by future generations.
Most studies suggest that around 0.8 percent of the U.S. and U.K. population is CIHHV6 positive, thus carrying a copy of HHV-6 in each cell. While most CIHHV-6 individuals appear healthy, they may be less able to defend themselves against other strains of HHV-6 that they might encounter. Medveczky reports that some of these individuals suffer from a CFS-like illness. In a cohort of CFS patients with serious neurological symptoms, the researchers found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public. In light of this finding, the authors of the study suggest naming this sub-category of CFS “Inherited Human Herpesvirus 6 Syndrome,” or IHS.
Medveczky’s team discovered that untreated CIHHV-6 patients with CFS showed signs that the HHV-6 virus was actively replicating: determined by the presence of HHV-6 messenger RNA (mRNA), a substance produced only when the virus is active. The team followed these patients during treatment, and discovered that the HHV-6 mRNA disappeared by the sixth week of antiviral therapy with valganciclovir, a drug used to treat closely related cytomegalovirus (HHV-5). Of note, the group also found that short-term treatment regimens, even up to three weeks, had little or no impact on the HHV-6 mRNA level.
The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6.
The USF-led study was supported by the HHV-6 Foundation and the National Institutes of Health.
Further studies are needed to confirm that immune dysregulation, along with subsequent chronic persistence of the HHV-6 virus, is the root cause of the IHS patients’ clinical symptoms, the researchers report.
Sudden Decline in Testosterone May Cause Parkinson’s Disease Symptoms in Men
The results of a new study by neurological researchers at Rush University Medical Center show that a sudden decrease of testosterone, the male sex hormone, may cause Parkinson’s like symptoms in male mice. The findings were recently published in the Journal of Biological Chemistry.
One of the major roadblocks for discovering drugs against Parkinson’s disease is the unavailability of a reliable animal model for this disease.
“While scientists use different toxins and a number of complex genetic approaches to model Parkinson’s disease in mice, we have found that the sudden drop in the levels of testosterone following castration is sufficient to cause persistent Parkinson’s like pathology and symptoms in male mice,” said Dr. Kalipada Pahan, lead author of the study and the Floyd A. Davis endowed professor of neurology at Rush. “We found that the supplementation of testosterone in the form of 5-alpha dihydrotestosterone (DHT) pellets reverses Parkinson’s pathology in male mice.”
“In men, testosterone levels are intimately coupled to many disease processes,” said Pahan. Typically, in healthy males, testosterone level is the maximum in the mid-30s, which then drop about one percent each year. However, testosterone levels may dip drastically due to stress or sudden turn of other life events, which may make somebody more vulnerable to Parkinson’s disease.
“Therefore, preservation of testosterone in males may be an important step to become resistant to Parkinson’s disease,” said Pahan.
Understanding how the disease works is important to developing effective drugs that protect the brain and stop the progression of Parkinson’s disease. Nitric oxide is an important molecule for our brain and the body.
"However, when nitric oxide is produced within the brain in excess by a protein called inducible nitric oxide synthase, neurons start dying,” said Pahan.
“This study has become more fascinating than we thought,” said Pahan. “After castration, levels of inducible nitric oxide synthase (iNOS) and nitric oxide go up in the brain dramatically. Interestingly, castration does not cause Parkinson’s like symptoms in male mice deficient in iNOS gene, indicating that loss of testosterone causes symptoms via increased nitric oxide production.”
“Further research must be conducted to see how we could potentially target testosterone levels in human males in order to find a viable treatment,” said Pahan.
Other researchers at Rush involved in this study were Saurabh Khasnavis, PhD, student, Anamitra Ghosh, PhD, student, and Avik Roy, PhD, research assistant professor.
This research was supported by a grant from the National Institutes of Health that received the highest score for its scientific merit in the particular cycle it was reviewed.
Parkinson’s is a slowly progressive disease that affects a small area of cells within the mid-brain known as the substantia nigra. Gradual degeneration of these cells causes a reduction in a vital chemical neurotransmitter, dopamine. The decrease in dopamine results in one or more of the classic signs of Parkinson’s disease that includes resting tremor on one side of the body; generalized slowness of movement; stiffness of limbs and gait or balance problems. The cause of the disease is unknown. Both environmental and genetic causes of the disease have been postulated.
Parkinson’s disease affects about 1.2 million patients in the United States and Canada. Although 15 percent of patients are diagnosed before age 50, it is generally considered a disease that targets older adults, affecting one of every 100 persons over the age of 60. This disease appears to be slightly more common in men than women.
(Source: rush.edu)
Migraine is Associated with Variations in Structure of Brain Arteries
The network of arteries supplying blood flow to the brain is more likely to be incomplete in people who suffer migraine, a new study by researchers in the Perelman School of Medicine at the University of Pennsylvania reports. Variations in arterial anatomy lead to asymmetries in cerebral blood flow that might contribute to the process triggering migraines.
The arterial supply of blood to the brain is protected by a series of connections between the major arteries, termed the “circle of Willis” after the English physician who first described it in the 17th century. People with migraine, particularly migraine with aura, are more likely to be missing components of the circle of Willis.
Migraine affects an estimated 28 million Americans, causing significant disability. Experts once believed that migraine was caused by dilation of blood vessels in the head, while more recently it has been attributed to abnormal neuronal signals. In this study, appearing in PLOS ONE, researchers suggest that blood vessels play a different role than previously suspected: structural alterations of the blood supply to the brain may increase susceptibility to changes in cerebral blood flow, contributing to the abnormal neuronal activity that starts migraine.
"People with migraine actually have differences in the structure of their blood vessels - this is something you are born with," said the study’s lead author, Brett Cucchiara, MD, Associate Professor of Neurology. "These differences seem to be associated with changes in blood flow in the brain, and it’s possible that these changes may trigger migraine, which may explain why some people, for instance, notice that dehydration triggers their headaches."
In a study of 170 people from three groups - a control group with no headaches, those who had migraine with aura, and those who had migraine without aura - the team found that an incomplete circle of Willis was more common in people with migraine with aura (73 percent) and migraine without aura (67 percent), compared to a headache-free control group (51 percent). The team used magnetic resonance angiography to examine blood vessel structure and a noninvasive magnetic resonance imaging method pioneered at the University of Pennsylvania, called Arterial spin labeling (ASL), to measure changes in cerebral blood flow.
"Abnormalities in both the circle of Willis and blood flow were most prominent in the back of the brain, where the visual cortex is located. This may help explain why the most common migraine auras consist of visual symptoms such as seeing distortions, spots, or wavy lines,” said the study’s senior author, John Detre, MD, Professor of Neurology and Radiology.
Both migraine and incomplete circle of Willis are common, and the observed association is likely one of many factors that contribute to migraine in any individual. The researchers suggest that at some point diagnostic tests of circle of Willis integrity and function could help pinpoint this contributing factor in an individual patient. Treatment strategies might then be personalized and tested in specific subgroups.
Bad night’s sleep? The moon could be to blame
Many people complain about poor sleep around the full moon, and now a report appearing in Current Biology, a Cell Press publication, on July 25 offers some of the first convincing scientific evidence to suggest that this really is true. The findings add to evidence that humans—despite the comforts of our civilized world—still respond to the geophysical rhythms of the moon, driven by a circalunar clock.
"The lunar cycle seems to influence human sleep, even when one does not ‘see’ the moon and is not aware of the actual moon phase," says Christian Cajochen of the Psychiatric Hospital of the University of Basel.
In the new study, the researchers studied 33 volunteers in two age groups in the lab while they slept. Their brain patterns were monitored while sleeping, along with eye movements and hormone secretions.
The data show that around the full moon, brain activity related to deep sleep dropped by 30 percent. People also took five minutes longer to fall asleep, and they slept for twenty minutes less time overall. Study participants felt as though their sleep was poorer when the moon was full, and they showed diminished levels of melatonin, a hormone known to regulate sleep and wake cycles.
"This is the first reliable evidence that a lunar rhythm can modulate sleep structure in humans when measured under the highly controlled conditions of a circadian laboratory study protocol without time cues," the researchers say.
Cajochen adds that this circalunar rhythm might be a relic from a past in which the moon could have synchronized human behaviors for reproductive or other purposes, much as it does in other animals. Today, the moon’s hold over us is usually masked by the influence of electrical lighting and other aspects of modern life.
The researchers say it would be interesting to look more deeply into the anatomical location of the circalunar clock and its molecular and neuronal underpinnings. And, they say, it could turn out that the moon has power over other aspects of our behavior as well, such as our cognitive performance and our moods.
Scientist discovers novel mechanism in spinal cord injury
More than 11,000 Americans suffer spinal cord injuries each year, and since over a quarter of those injuries are due to falls, the number is likely to rise as the population ages. The reason so many of those injuries are permanently disabling is that the human body lacks the capacity to regenerate nerve fibers. The best our bodies can do is route the surviving tissue around the injury site.
"It’s like a detour after an earthquake," says Kuo-Fen Lee, the Salk Institute’s Helen McLoraine Chair in Molecular Neurobiology. "If the freeway is down, but you can still take the side-streets, traffic can still move. So your strategy has to be to find a way to preserve as much tissue as possible, to give yourself a chance for that rerouting."
In a paper published in this week’s PLOS ONE, Lee and his colleagues describe how a protein named P45 may yield insight into a possible molecular mechanism to promote rerouting for spinal cord healing and functional recovery. Because injured mice can recover more fully than human beings, Lee sought the source of the difference. He discovered that P45 had a previously unknown neuroprotective effect.
"As a biochemist and neurobiologist, this discovery gives me hope that we can find a potential target molecule for drug treatments," says Lee. "Nevertheless, I must caution that this is only the first step in knowing what to look for."
In a human or a mouse, the success of an attempted rerouting after a spinal cord injury depends on how much healthy tissue is left. But wounds set off a cascade of reactions within cells, which if not stopped in time will result in more dead and dying tissue extending beyond the injury site. Nerve traction from the injury site leads to disconnection of the network required for normal sensory and motor functions. Lee found that P45 is the key factor determining whether the cascade continues on to its destructive end.
A complex of proteins, by sequentially interacting with each other, induces this cascade of cell death. Lee discovered that P45 is a natural antagonist to this process. Antagonists are molecules, some naturally occurring, some made in pharmaceutical laboratories, that work essentially like sticking gum in a lock. Because the antagonist is in place, no other molecule can get in. In this case, P45 prevents two other proteins in the death cascade from connecting, rendering their actions harmless and stopping cell death.
But there’s more to how P45 works that gives Lee hope that he may be on to a unique approach to finding new ways to treat spinal cord injuries. In other recent findings, which are being prepared for publication, his team saw P45 also yield positive effects, specifically the encouragement of healthy tissue growth. Thus, Lee concludes its real role may be as a sort of “see-saw” molecule that tips the balance in the cascade from negative to positive.
"The great thing about P45 is that it can both inhibit the negative by blocking the conformational change that would lead to more cell death, while promoting the positive-the survival and growth of tissue-thus making it easier to foster recovery following spinal cord injury," Lee explains.
"If you can understand where you could tilt the balance of positive/negative signal, it would give you less damage while helping to promote healing," says Lee. "It could be combinatorial-maybe one molecule can do both, or maybe it’s a combination of two molecules, one to negate, one to promote. The hope is if such a control switch could be found, more tissue could be preserved at the site of injury, thus increasing the chances that movement might someday be restored."
The next step for Lee’s laboratory will be to seek either a gene, or a process that works in a similar see-saw way in humans, or can be made to work with therapeutic intervention. Still, Lee cautions, this remains a proof of concept experiment in mice. Even if such a mechanism were found in humans, clinical applications would be years away.
Key target responsible for triggering detrimental effects in brain trauma identified
Researchers studying a type of cell found in the trillions in our brain have made an important discovery as to how it responds to brain injury and disease such as stroke. A University of Bristol team has identified proteins which trigger the processes that underlie how astrocyte cells respond to neurological trauma.
The star-shaped astrocytes, which outnumber neurons in humans, are a type of glial cell that comprise one of two main categories of cell found in the brain along with neurons. The cells, which have branched extensions that reach synapses (the connections between neurons) blood vessels, and neighbouring astrocytes, play a pivotal role in almost all aspects of brain function by supplying physical and nutritional support for neurons. They also contribute to the communication between neurons and the response to injury.
However, the cells are also known to trigger both beneficial and detrimental effects in response to neurological trauma. When the brain is subjected to injury or disease, the cells react in a number of ways, including a change in shape. In severe cases, the altered cells form a scar, which is thought to have beneficial, as well as detrimental effects by allowing prompt repair of the blood-brain barrier, and limiting cell death, but also impairing the regeneration of nerve fibres and the effective incorporation of neuronal grafts - where additional neuronal cells are added to the injured site.
The cells change shape via the regulation of a structural component of the cell called the actin cytoskeleton, which is made up of filaments that shrink and grow to physically manoeuvre parts of the cell. In the lab, the team cultured astrocytes in a dish and were able to make them change shape by chemically or genetically manipulating proteins that control actin, and also by mimicking the environment that the cells would be exposed to during a stroke.
By doing so the team found that very dramatic changes in cell shape were caused by controlling the actin cytoskeleton in the in vitro stroke model. The team also identified additional protein molecules that control this process, suggesting that a complex mechanism is involved.
Dr Jonathan Hanley from the University’s School of Biochemistry said: “Our findings are crucial to our understanding of how the brain responds to many disorders that affect millions of people every year. Until now, the details of the actin-based mechanisms that control astrocyte morphology were unknown, so we anticipate that our work will lead to future discoveries about this important process.”
(Source: eurekalert.org)
Researchers discover how brain cells change their tune
Brain cells talk to each other in a variety of tones. Sometimes they speak loudly but other times struggle to be heard. For many years scientists have asked why and how brain cells change tones so frequently. Today National Institutes of Health researchers showed that brief bursts of chemical energy coming from rapidly moving power plants, called mitochondria, may tune brain cell communication.
"We are very excited about the findings," said Zu-Hang Sheng, Ph.D., a senior principal investigator and the chief of the Synaptic Functions Section at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS). "We may have answered a long-standing, fundamental question about how brain cells communicate with each other in a variety of voice tones."
The network of nerve cells throughout the body typically controls thoughts, movements and senses by sending thousands of neurotransmitters, or brain chemicals, at communication points made between the cells called synapses. Neurotransmitters are sent from tiny protrusions found on nerve cells, called presynaptic boutons. Boutons are aligned, like beads on a string, on long, thin structures called axons. They help control the strength of the signals sent by regulating the amount and manner that nerve cells release transmitters.
Mitochondria are known as the cell’s power plant because they use oxygen to convert many of the chemicals cells use as food into adenosine triphosphate (ATP), the main energy that powers cells. This energy is essential for nerve cell survival and communication. Previous studies showed that mitochondria can rapidly move along axons, dancing from one bouton to another.
In this study, published in Cell Reports, Dr. Sheng and his colleagues show that these moving power plants may control the strength of the signals sent from boutons.
"This is the first demonstration that links the movement of mitochondria along axons to a wide variety of nerve cell signals sent during synaptic transmission," said Dr. Sheng.
The researchers used advanced microscopic techniques to watch mitochondria move among boutons while they released neurotransmitters. They found that boutons sent consistent signals when mitochondria were nearby.
"It’s as if the presence of mitochondria causes a bouton to talk in a monotone voice," said Tao Sun, Ph.D., a researcher in Dr. Sheng’s laboratory and the first author of the study.
Surprisingly, when the mitochondria were missing or moving away from boutons, the signal strength fluctuated. The results suggested that the presence of stationary power plants at synapses controls the stability of the nerve signal strength.
To test this idea further, the researchers manipulated mitochondrial movement in axons by changing levels of syntaphilin, a protein that helps anchor mitochondria to the nerve cell’s skeleton found inside axons. Removal of syntaphilin resulted in faster moving mitochondria and electrical recordings from these neurons showed that the signals they sent fluctuated greatly. Conversely, elevating syntaphilin levels in nerve cells arrested mitochondrial movement and resulted in boutons that spoke in monotones by sending signals with the same strength.
"It’s known that about one third of all mitochondria in axons move. Our results show that brain cell communication is tightly controlled by highly dynamic events occurring at numerous tiny cell-to-cell connection points," said Dr. Sheng.
In separate experiments the researchers watched ATP energy levels in these tiny boutons as they sent nerve messages.
"The levels fluctuated more in boutons that did not have mitochondria nearby," said Dr. Sun.
The researchers also found that blocking ATP production in mitochondria with the drug oligomycin reduced the size of the signals boutons sent even if a mitochondrial power plant was nearby.
"Our results suggest that local ATP production by nearby mitochondria is critical for consistent neurotransmitter release," said Dr. Sheng. "It appears that variability in synaptic transmission is controlled by rapidly moving mitochondria which provide brief bursts of energy to the boutons they pass through."
Problems with mitochondrial energy production and movement throughout nerve cells have been implicated in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and other major neurodegenerative disorders. Dr. Sheng thinks these results will ultimately help scientists understand how these problems can lead to disorders in brain cell communication.
"Our findings reveal the cellular mechanisms that tune brain communication by regulating mitochondrial mobility, thus advancing our understanding of human neurological disorders," said Dr. Sheng.