Posts tagged synapses
Articles and news from the latest research reports.
Scientists advance understanding of brain receptor; may help fight neurological disorders
For several years, the pharmaceutical industry has tried to develop drugs that target a specific neurotransmitter receptor in the brain, the NMDA receptor. This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression.
But drug companies have had little success developing clinically effective drugs that target this receptor.
Now, researchers at Oregon Health & Science University’s Vollum Institute believe they may understand why. And what they’ve discovered may help in the development of new therapies for these conditions.
In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties.
As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action.
What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts.
"What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn’t there in high quantities. The target they’ve been looking for isn’t the target that’s there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar’s co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory.
Tovar said these findings could provide a new target for drug development.
"If you know what’s there, then you know what to go after — you just have to figure out how to do it," Tovar said.
The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial.
"NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said.
"From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective."
(Image: iStockphoto)
Down syndrome neurons grown from stem cells show signature problems
Down syndrome, the most common genetic form of intellectual disability, results from an extra copy of one chromosome. Although people with Down syndrome experience intellectual difficulties and other problems, scientists have had trouble identifying why that extra chromosome causes such widespread effects.
In new research published this week, Anita Bhattacharyya, a neuroscientist at the Waisman Center at UW-Madison, reports on brain cells that were grown from skin cells of individuals with Down syndrome.
"Even though Down syndrome is very common, it’s surprising how little we know about what goes wrong in the brain," says Bhattacharyya. "These new cells provide a way to look at early brain development."
The study began when those skin cells were transformed into induced pluripotent stem cells, which can be grown into any type of specialized cell. Bhattacharyya’s lab, working with Su-Chun Zhang and Jason Weick, then grew those stem cells into brain cells that could be studied in the lab.
One significant finding was a reduction in connections among the neurons, Bhattacharyya says. “They communicate less, are quieter. This is new, but it fits with what little we know about the Down syndrome brain.” Brain cells communicate through connections called synapses, and the Down neurons had only about 60 percent of the usual number of synapses and synaptic activity. “This is enough to make a difference,” says Bhattacharyya. “Even if they recovered these synapses later on, you have missed this critical window of time during early development.”
The researchers looked at genes that were affected in the Down syndrome stem cells and neurons, and found that genes on the extra chromosome were increased 150 percent, consistent with the contribution of the extra chromosome.
However, the output of about 1,500 genes elsewhere in the genome was strongly affected. “It’s not surprising to see changes, but the genes that changed were surprising,” says Bhattacharyya. The predominant increase was seen in genes that respond to oxidative stress, which occurs when molecular fragments called free radicals damage a wide variety of tissues.
"We definitely found a high level of oxidative stress in the Down syndrome neurons," says Bhattacharyya. "This has been suggested before from other studies, but we were pleased to find more evidence for that. We now have a system we can manipulate to study the effects of oxidative stress and possibly prevent them."
Down syndrome includes a range of symptoms that could result from oxidative stress, Bhattacharyya says, including accelerated aging. “In their 40s, Down syndrome individuals age very quickly. They suddenly get gray hair; their skin wrinkles, there is rapid aging in many organs, and a quick appearance of Alzheimer’s disease. Many of these processes may be due to increased oxidative stress, but it remains to be directly tested.”
Oxidative stress could be especially significant, because it appears right from the start in the stem cells. “This suggests that these cells go through their whole life with oxidative stress,” Bhattacharyya adds, “and that might contribute to the death of neurons later on, or increase susceptibility to Alzheimer’s.”
Other researchers have created neurons with Down syndrome from induced pluripotent stem cells, Bhattacharyya notes. “However, we are the first to report this synaptic deficit, and to report the effects on genes on other chromosomes in neurons. We are also the first to use stem cells from the same person that either had or lacked the extra chromosome. This allowed us to look at the difference just caused by extra chromosome, not due to the genetic difference among people.”
The research, published the week of May 27 in the Proceedings of the National Academy of Sciences, was a basic exploration of the roots of Down syndrome. Bhattacharyya says that while she did not intend to explore treatments in the short term, “we could potentially use these cells to test or intelligently design drugs to target symptoms of Down syndrome.”
(Source: news.wisc.edu)
Scientists discover the origin of a giant synapse
Humans and most mammals can determine the spatial origin of sounds with remarkable acuity. We use this ability all the time—crossing the street; locating an invisible ringing cell phone in a cluttered bedroom. To accomplish this small daily miracle, the brain has developed a circuit that’s rapid enough to detect the tiny lag that occurs between the moment the auditory information reaches one of our ears, and the moment it reaches the other. The mastermind of this circuit is the “Calyx of Held,” the largest known synapse in the brain. EPFL scientists have revealed the role that a certain protein plays in initiating the growth of these giant synapses.
The discovery, published in Nature Neuroscience, could also help shed light on a number of neuropsychiatric disorders.
Enormous synapses enable faster communication
Ordinarily, neurons have thousands of contact points – known as synapses - with neighboring neurons. Within a given time frame, a neuron has to receive several signals from its neighbors in order to be able to fire its own signal in response. Because of this, information passes from neuron to neuron in a relatively random manner.
In the auditory part of the brain, this is not the case. Synapses often grow to extremely large sizes, and these behemoths are known as “Calyx of Held” synapses. Because they have hundreds of contact points, they are capable of transmitting a signal singlehandedly to a neighboring neuron. “It’s almost like peer-to-peer communication between neurons,” explains EPFL professor Ralf Schneggenburger, who led the study. The result is that information is processed extremely quickly, in a few fractions of a millisecond, instead of the slower pace of more than 10 milliseconds that occurs in most other neuronal circuits.
Identifying the protein
To isolate the protein responsible for controlling the growth of this gigantic synapse, the scientists had to perform painstaking research. Using methods for analyzing gene expression in mice, they identified several members of the “BMP” family of proteins from among more than 20,000 possible candidates.
To verify that they had truly identified the right protein, the researchers disabled BMP protein receptors in the auditory part of a mouse brain. “The resulting electrophysiological signal of the Calyx of Held was significantly altered,” explains Le Xiao, first author on the study. “This would suggest a large anatomical difference.”
The scientists then reconstructed the synapses in three dimensions from slices that were observed under an electron microscope. Instead of a single, massive Calyx of Held, which would encompass nearly half the neuron, the 3D image of the neuron clearly shows several, smaller synapses. “This shows that the process involving the BMP protein not only causes that one synapse to grow, but also performs a selection, by eliminating the others,” says Schneggenburger.
Synaptic connectivity, the key to many psychiatric puzzles
The impact of this study will go well beyond increasing our understanding of the auditory system. The results suggest that the BMP protein plays an important role in developing connectivity in the brain. Schneggenburger and his colleagues are currently investigating its role elsewhere in the brain. “Some neuropsychiatric disorders, such as schizophrenia and autism, are characterized by the abnormal development of synaptic connectivity in certain key parts of the brain,” explains Schneggenburger. By identifying and explaining the role of various proteins in this process, the scientists hope to be able to shed more light on these poorly understood disorders.
Researchers identify how cells control calcium influx
When brain cells are overwhelmed by an influx of too many calcium molecules, they shut down the channels through which these molecules enter the cells. Until now, the “stop” signal mechanism that cells use to control the molecular traffic was unknown.
In the new issue of the journal Neuron, UC Davis Health System scientists report that they have identified the mechanism. Their findings are relevant to understanding the molecular causes of the disruption of brain functioning that occurs in stroke and other neurological disorders.
"Too much calcium influx clearly is part of the neuronal dysfunction in Alzheimer’s disease and causes the neuronal damage during and after a stroke. It also contributes to chronic pain," said Johannes W. Hell, professor of pharmacology at UC Davis. Hell headed the research team that identified the mechanism that stops the flow of calcium molecules, which are also called ions, into the specialized brain cells known as neurons.
Hell explained that each day millions of molecules of calcium enter and exit each of the 100 billion neurons of the human brain. These calcium ions move in and out of neurons through pore-like structures, known as channels, that are located in the outer surface, or “skin,” of each cell.
The flow of calcium ions into brain cells generates the electrical impulses needed to stimulate such actions as the movement of muscles in our legs and the creation of new memories in the brain. The movement of calcium ions also plays a role in gene expression and affects the flexibility of the structures, called synapses, that are located between neurons and transmit electrical or chemical signals of various strengths from one cell to a second cell.
Neurons employ an unexpected and highly complex mechanism to down regulate, or reduce, the activity of channels that are permitting too many calcium ions to enter neurons, Hell and his colleagues discovered. The mechanism, which leads to the elimination of the overly permissive ion channel employs two proteins, α-actinin and the calcium-binding messenger protein calmodulin.
Located on the neuron’s outer surface, referred to as the plasma membrane, α-actinin stabilizes the type of ion channels that constitute a major source of calcium ion influx into brain cells, Hell explained. This protein is a component of the cytoskeleton, the scaffolding of cells. The ion channels that are a major source of calcium ions are referred to as Cav1.2 (L type voltage-dependent calcium channels).
The researchers also found that the calcium-binding messenger protein calmodulin, which is the cell’s main sensor for calcium ions, induces internalization, or endocytosis, of Cav1.2 to remove this channel from the cell surface, thus providing an important negative feedback mechanism for excessive calcium ion influx into a neuron, Hell explained.
The discovery that α-actinin and calmodulin play a role in controlling calcium ion influx expands upon Hell’s previous research on the molecular mechanisms that regulate the activity of various ion channels at the synapse.
One previous study proved relevant to understanding the biological mechanisms that underlie the body’s fight-or-flight response during stress.
In work published in the journal Science in 2001, Hell and colleagues reported that the regulation of Cav1.2 by adrenergic signaling during stress is performed by one of the adrenergic receptors (beta 2 adrenergic receptor) directly linked to Cav1.2.
"This protein-protein interaction ensures that the adrenergic regulation is fast, efficient and precisely targets this channel," Hell said.
"We showed that Cav1.2 is regulated by adrenergic signaling on a time scale of a few seconds, and this is mainly increasing its activity when needed, for example during danger, to make our brain work faster and better. The same channel is in the heart, where adrenergic stimulation increases channel/Ca influx activity, increasing the pacing and strength of our heart beat to meet the increased physical demands during danger."
(Source: universityofcalifornia.edu)
Scientists identify important regulator for synapse stability and plasticity
Using the fruit fly as a model organism, neurobiologists from the Friedrich Miescher Institute for Biomedical Research have identified the L1-type CAM neuroglian as an important regulator for synapse growth, function and stability. They show that the interaction of neuroglian with ankyrin provides a regulatory module to locally control synaptic connectivity and function.
A Drosophila neuromuscular junction. Motoneuron membrane (blue), synaptic vesicles (green), postsynaptic density (red)
From its earliest beginnings until an organism’s death, the nervous system changes. Connections between nerve cells are formed, stabilized and disassembled not only during the development of the brain in the womb and in early childhood, but also in adults as they learn or form memories. In this flow of change, cell adhesion molecules (CAMs), which mediate cell-cell interactions, are thought to provide stability and guidance in a Velcro-like-manner as synapses change.
Jan Pielage and his group at the Friedrich Miescher Institute for Biomedical Research have carried out an unbiased genetic screen to identify cell adhesion molecules that control synapse maintenance and plasticity, using the fruit fly, Drosophila. As they publish in the latest issue of PLOS Biology, they identified the cell adhesion molecule called neuroglian as a key regulator for synapse stability.
Neuroglian is a transmembrane protein with a large extracellular domain and an intracellular signaling domain. Through the extracellular domain interactions with CAMs on neighboring cells are established. This stabilizes the site and is a prerequisite for synapse formation. “We think that the extracellular interactions of neuroglian are essential for neurite outgrowth and axon targeting during early development,” explains Pielage.
The scientists could then show that the intracellular domain, which interacts with the adaptor molecule called ankyrin, modulates the stability of synapses. At the neuromuscular junction, where nerve cells innervate the muscle, the strength of the interaction of neuroglian with ankyrin modulates the balance between synapse growth and stability. As the binding affinity of ankyrin for neuroglian decreased, e.g. due to phosphorylation, the mobility of neuroglian within the motorneuron increased. This change in mobility caused the destabilization of synapses but at the same time, it allowed the formation of new synapses at other places. “This organization permits easy regulation, and allows the fine tuning of synaptic connectivity along one nerve cell without disrupting the neuronal network or impairing overall circuit stability,” said Pielage.
In the central nervous system, where synapses are formed between two neurons, a homophilic interaction of neuroglian is required to establish the contact between pre- and postsynaptic neurons. A differential regulation of ankyrin binding is then necessary to coordinate transsynaptic development and to enable synapse maturation and function. “Modulation of the neuroglian-ankyrin interaction might enable local and precise control of synaptic connectivity,” comments Pielage.
This comprehensive structure function study provides a molecular basis for previous observations linking mutations in the ankyrin binding domain of the human homologue of neuroglian, L1CAM, to neurological L1/CRASH disorders that include mental retardation.
(Source: fmi.ch)
Structural dynamics underlying memory in aging brains
When the brains of those who have succumbed to age-related neurodegeneration are analyzed post-mortem, they typically show significant atrophy on all scales. Not only is the cortex thinner and sparser, but the hollow ventricles inside the brain are grossly enlarged. In the absence of any specific disease, these general trends are still familiar. It has traditionally been assumed that the dynamic microfeatures of aged brains—the growth of the fine neurites and the synapses they make—would similarly be degenerate. In other words, synaptic growth would have either entered some form of stasis, or alternatively, a state of permanent decay with replacement by matrix or scar tissue. Contrary to these expectations, recent research shows increased structural plasticity in the axonal component of synapses in the aged mouse cortex. Reporting in the current issues of PNAS, researchers provide evidence that the observed behavioral deficits in these animals may be due to an inability to maintain persistent synaptic structure, rather than because of a loss of plasticity.
Specifically, the researchers found dramatic increases in the rates of synapse formation and elimination. They used two-photon microscopy to image axonal arbors and boutons in aged brains over time. Compared to young adult brains, established synaptic boutons in aged brain showed 10-fold higher rates of destabilization, and 20-fold higher turnover. The researchers also demonstrated, that while the size and density of synapses was comparable, size fluctuations were significantly higher in the aged brains.
Changes in synaptic structure are believed to be the mechanism for encoding long-term memory in the brain. In the absence of the full molecular picture underlying the way they change and grow, macroscopic appearance (size) is a convenient stand-in used to gauge relative importance of a particular synapse. Among other things, a larger synapse has greater resource at its disposal to reliably match incoming spikes to transmitter release. Not only can a larger synapse generally do this matching faster, they can do it for a longer time. The new studies suggest, however, that decreased ability to form new memories, or learn new behaviors, results from synapses being too fickle, rather than from loss of flexibility.
Clearly the full behavior of synapses is far from understood, despite it being one of the central preoccupations of experimental neuroscience. It is generally believed that the average synapse is at best able to match an incoming spike with fusion of a vesicle (and subsequent transmitter release) roughly half of the time. Many theoretical efforts have been made to account for this fact. One approach has been to do a strict accounting analysis of the energetic use of ATP by a neuron’s entire signalling tree. In other words, estimate how a neuron partitions its ATP budget between transmitting information in the form of spikes down the axon, and that spent in completing the hand-off to the next neuron at the synapse.
Detailed and painstaking measurements of axonal structural dynamics, as done here by the authors, is critical ground-floor work towards understand neural circuits. Isolated molecular details, while important, will never be sufficient to completely understand how learning and memory emerge from architectural changes. The current efforts of the BRAIN Initiative to map the complete connectome of a brain, together with a full activity map, will also need to include efforts to create what might be called, a theory of neurons. The ways in which neurons budget their energy, is likely to a central component of such a theory.
As a start, one postulate of a theory of neurons, that is consistent with the one-half probability for synaptic information transfer, might be the following: neurons tend to match the energy spent in sending spikes through their entire axonal arbor, with the sum total of the energy spent at all terminal boutons of that axon. The temporal aspects of how synapses are generated and eliminated in a short-lived animal, like a mouse, may be far different than those in a human. Understanding how these processes change with age, and with the amount of energy available to synapses to effect that change, will help complete the larger picture.
(Source: medicalxpress.com)
First steps of synapse building captured in live zebra fish embryos
Using spinning disk microscopy on barely day-old zebra fish embryos, University of Oregon scientists have gained a new window on how synapse-building components move to worksites in the central nervous system.
What researchers captured in these see-through embryos — in what may be one of the first views of early glutamate-driven synapse formation in a living vertebrate — were orderly movements of protein-carrying packets along axons to a specific site where a synapse would be formed.
Washbourne addresses:
► The basic importance of the findings
► The connection to diseases, including autism
The discovery, in research funded by the National Institutes of Health, is described in a paper placed online ahead of publication in the April 25 issue of the open-access journal Cell Reports. It is noteworthy because most synapses formed in vertebrates use glutamate as a neurotransmitter, and breakdowns in the process have been tied to conditions such as autism, schizophrenia and mental retardation.
The zebra fish has become one of the leading research models for studying early development, in general, and human-disease states.
In this case, researchers used immunofluorescence labeling to highlight the area they put under the microscopes. The embryos they studied were barely 24-hours old and a millimeter in length, but neurons in their spinal cord were already forming connections called synapses. Images were taken every 30 seconds over two hours.
"If we zoom out a bit and look at development in the human, the majority of synapse formation occurs in the cortex after birth and continues for the first two years in a baby’s life," said Philip Washbourne, a professor of biology and member of the UO’s Institute of Neuroscience.
Previous studies, done in vitro, contradicted each other, with one, in 2000, identifying a single packet of building blocks arriving at a pre-synaptic terminal. The other, in 2004, identified two protein packets. After watching the process unfold live, with imaging over long time spans, Washbourne said: “We now see at least three, and maybe more, such deliveries.”
"Axons are long processes — think of them as highways — of neurons. In humans, these can be a meter long, from spinal cord to your big toe," he said. It’s in the cell body where all the proteins are made, and they have to be transported out. Is it done by a single bus or by several cars? These results point to additional layers of complexity in the established mechanisms of synaptogenesis."
The new research also showed that sequence also is crucial. Two different pre-synaptic packages of molecules repeatedly arrived in the same order. A key building block — the protein synapsin — always arrived third. As these delivery vehicles traveled the axonal highway, another protein, a cyclin-dependent kinase known as Cdk5, acts as a stoplight at the synapse-construction site, where phosphorylation occurs. More research is needed on Cdk5, Washbourne said.
"Understanding how all this happens will inform us to what’s going wrong in neurodevelopment that leads to diseases," Washbourne said. "We have indications that the glue that gets all this going includes a gene that has been linked to autism, so knowing how these molecules start the process of synapse formation — and what goes wrong in people with mutations in these genes — might allow for a therapeutic targeting to correct the mutations and manipulate the stop signs."
Discovery of genetic defect which triggers epilepsy
Researchers at the University Department of Neurology at the MedUni Vienna have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. With the so-called “next generation sequencing”, with which genetic changes can be identified within a few days, it was ascertained that the CNTN2 gene is defective in this type of epilepsy.
This was investigated by a team led by Elisabeth Stögmann in collaboration with Cairo’s Ain Shams University and the Helmholtz Centre Munich with reference to a particular Egyptian family, in which five sick children have resulted from the marriage of one healthy cousin to his, likewise healthy, second cousin. The children affected suffer from a specific epilepsy syndrome, in which different types of epileptic attacks occur. This constellation has the “advantage”, according to Stögmann, that both alleles of the gene, which is how one designates different forms of the gene, demonstrate this defect: “As a result the defect becomes symptomatic and identifiable.
"20,000 to 25,000 genes, including all the "protein coding" ones, were sequenced for this. When this was done a mutation was found in the CNTN2 gene. CNTN2 undertakes an important function in the anchoring of potassium channels to the synapses. The mutation makes it no longer possible to generate this protein and, as a consequence, the potassium channels no longer remain affixed to the synapses. The researchers suspect that the epilepsy in this family is triggered by the altered function of the potassium channels.
This discovery, which has now been published in the top journal “Brain”, is providing the stimulus for further research to investigate this particular gene in other epilepsy patients as well. Approximately one percent of the population suffers from active epilepsy in which regular epileptic fits occur. The danger of suffering from an epileptic fit once in your life lies at approximately four to five percent. Genetic factors play a major part in the occurrence of epilepsies.
(Source: meduniwien.ac.at)
Even mild traumatic brain injuries can kill brain tissue
Scientists have watched a mild traumatic brain injury play out in the living brain, prompting swelling that reduces blood flow and connections between neurons to die.
“Even with a mild trauma, we found we still have these ischemic blood vessels and, if blood flow is not returned to normal, synapses start to die,” said Dr. Sergei Kirov, neuroscientist and Director of the Human Brain Lab at the Medical College of Georgia at Georgia Regents University.
They also found that subsequent waves of depolarization – when brain cells lose their normal positive and negative charge – quickly and dramatically increase the losses.
Researchers hope the increased understanding of this secondary damage in the hours following an injury will point toward better therapy for the 1.7 million Americans annually experiencing traumatic brain injuries from falls, automobile accidents, sports, combat and the like. While strategies can minimize impact, no true neuroprotective drugs exist, likely because of inadequate understanding about how damage unfolds after the immediate impact.
Kirov is corresponding author of a study in the journal Brain describing the use of two-photon laser scanning microscopy to provide real-time viewing of submicroscopic neurons, their branches and more at the time of impact and in the following hours.
Scientists watched as astrocytes – smaller cells that supply neurons with nutrients and help maintain normal electrical activity and blood flow – in the vicinity of the injury swelled quickly and significantly. Each neuron is surrounded by several astrocytes that ballooned up about 25 percent, smothering the neurons and connective branches they once supported.
“We saw every branch, every small wire and how it gets cut,” Kirov said. “We saw how it destroys networks. It really goes downhill. It’s the first time we know of that someone has watched this type of minor injury play out over the course of 24 hours.”
Stressed neurons ran out of energy and became silent but could still survive for hours, potentially giving physicians time to intervene, unless depolarization follows. Without sufficient oxygen and energy, internal pumps that ensure proper polarity by removing sodium and pulling potassium into neurons, can stop working and dramatically accelerate brain-cell death.
“Like the plus and minus ends of a battery, neurons must have a negative charge inside and a positive charge outside to fire,” Kirov said. Firing enables communication, including the release of chemical messengers called neurotransmitters.
“If you have six hours to save tissue when you have just lost part of your blood flow, with this spreading depolarization, you lose tissue within minutes,” he said.
While common in head trauma, spreading depolarization would not typically occur in less-traumatic injuries, like his model. His model was chemically induced to reveal more about how this collateral damage occurs and whether neurons could still be saved. Interestingly, researchers found that without the initial injury, brain cells completely recovered after re-polarization but only partially recovered in the injury model.
While very brief episodes of depolarization occur as part of the healthy firing of neurons, spreading depolarization exacerbates the initial traumatic brain injury in more than half of patients and results in poor prognosis, previous research has shown. However, a 2011 review in the journal Nature Medicine indicated that short-lived waves can actually protect surrounding brain tissue. Kirov and his colleagues wrote that more study is needed to determine when to intervene.
One of Kirov’s many next steps is exploring the controversy about whether astrocytes’ swelling in response to physical trauma is a protective response or puts the cells in destruct mode. He also wants to explore better ways to protect the brain from the growing damage that can follow even a slight head injury.
Currently, drugs such as diuretics and anti-seizure medication may be used to help reduce secondary damage of traumatic brain injury. Astrocytes can survive without neurons but the opposite is not true, Kirov said. The ratio of astrocytes to neurons is higher in humans and human astrocytes are more complex, Kirov said.
Star-Shaped Glial Cells Act as the Brain’s “Motherboard”
The transistors and wires that power our electronic devices need to be mounted on a base material known as a “motherboard.” Our human brain is not so different — neurons, the cells that transmit electrical and chemical signals, are connected to one another through synapses, similar to transistors and wires, and they need a base material too.
But the cells serving that function in the brain may have other functions as well. PhD student Maurizio De Pittà of Tel Aviv University’s Schools of Physics and Astronomy and Electrical Engineering says that astrocytes, the star-shaped glial cells that are predominant in the brain, not only control the flow of information between neurons but also connect different neuronal circuits in various regions of the brain.
Using models designed to mimic brain signalling, De Pittà’s research, led by his TAU supervisor Prof. Eshel Ben-Jacob, determined that astrocytes are actually “smart” in addition to practical. They integrate all the different messages being transferred through the neurons and multiplexing them to the brain’s circuitry. Published in the journal Frontiers in Computational Neuroscience and sponsored by the Italy-Israel Joint Neuroscience Lab, this research introduces a new framework for making sense of brain communications — aiding our understanding of the diseases and disorders that impact the brain.
Transcending boundaries
"Many pathologies are related to malfunctions in brain connectivity," explains Prof. Ben-Jacob, citing epilepsy as one example. "Diagnosis and the development of therapies rely on understanding the network of the brain and the source of undesirable activity."
Connectivity in the brain has traditionally been defined as point-to-point connections between neurons, facilitated by synapses. Astrocytes serve a protective function by encasing neurons and forming borders between different areas of the brain. These cells also transfer information more slowly, says Prof. Ben-Jacob — one-tenth of a second compared to one-thousandth of a second in neurons — producing signals that carry larger amounts of information over longer distances. Aastrocytes can transfer information regionally or spread it to different areas throughout the brain — connecting neurons in a different manner than conventional synapses.
De Pittà and his fellow researchers developed computational models to look at the different aspects of brain signalling, such as neural network electrical activity and signal transfer by synapses. In the course of their research, they discovered that astrocytes actually take an active role in the way these signals are distributed, confirming theories put forth by leading experimental scientists.
Astrocytes form additional networks to those of the neurons and synapses, operating simultaneously to co-ordinate information from different regions of the brain — much like an electrical motherboard functions in a computer, or a conductor ensuring that the entire orchestra is working in harmony, explains De Pittà.
These findings should encourage neuroscientists to think beyond neuron-based networks and adopt a more holistic view of the brain, he suggests, noting that the two communication systems are actually interconnected, and the breakdown of one can certainly impact the other. And what may seem like damage in one small area could actually be carried to larger regions.
A break in communication
According to Prof. Ben-Jacob, a full understanding of the way the brain sends messages is significant beyond satisfying pure scientific curiosity. Many diseases and disorders are caused by an irregularity in the brain’s communication system or by damage to the glial cells, so more precise information on how the network functions can help scientists identify the cause or location of a breakdown and develop treatments to overcome the damage.
In the case of epilepsy, for example, the networks frequently become overexcited. Alzheimer’s disease and other memory disorders are characterized by a loss of cell-to-cell connection. Further understanding brain connectivity can greatly aid research into these and other brain-based pathologies.