Posts tagged synapse formation
Articles and news from the latest research reports.
(Image caption: Part of a brain slice in which a transplanted induced neural stem cell is fully integrated in the neuronal network of the brain (blue) to develop into a complex and functional neuron.)
Implanted Neurons become Part of the Brain
Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have grafted neurons reprogrammed from skin cells into the brains of mice for the first time with long-term stability. Six months after implantation, the neurons had become fully functionally integrated into the brain. This successful, because lastingly stable, implantation of neurons raises hope for future therapies that will replace sick neurons with healthy ones in the brains of Parkinson’s disease patients, for example. The Luxembourg researchers published their results in the current issue of ‘Stem Cell Reports’.
The LCSB research group around Prof. Dr. Jens Schwamborn and Kathrin Hemmer is working continuously to bring cell replacement therapy to maturity as a treatment for neurodegenerative diseases. Sick and dead neurons in the brain can be replaced with new cells. This could one day cure disorders such as Parkinson’s disease. The path towards successful therapy in humans, however, is long. “Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction,” declares stem cell researcher Prof. Schwamborn, who heads a group of 15 scientists at LCSB.
In their latest tests, the research group and colleagues from the Max Planck Institute and the University Hospital Münster and the University of Bielefeld succeeded in creating stable nerve tissue in the brain from neurons that had been reprogrammed from skin cells. The stem cell researchers’ technique of producing neurons, or more specifically induced neuronal stem cells (iNSC), in a petri dish from the host’s own skin cells considerably improves the compatibility of the implanted cells. The treated mice showed no adverse side effects even six months after implantation into the hippocampus and cortex regions of the brain. In fact it was quite the opposite – the implanted neurons were fully integrated into the complex network of the brain. The neurons exhibited normal activity and were connected to the original brain cells via newly formed synapses, the contact points between nerve cells.
The tests demonstrate that the scientists are continually gaining a better understanding of how to treat such cells in order to successfully replace damaged or dead tissue. “Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson’s patients – namely the dopamine-producing neurons,” Schwamborn reports. In future, implanted neurons could produce the lacking dopamine directly in the patient’s brain and transport it to the appropriate sites. This could result in an actual cure, as has so far been impossible. The first trials in mice are in progress at the LCSB laboratories on the university campus Belval.
Team Sheds New Light on Nerve Cell Growth
Amidst the astounding complexity of the billions of nerve cells and trillions of synaptic connections in the brain, how do nerve cells decide how far to grow or how many connections to build? How do they coordinate these events within the developing brain?
In a new study, scientists from the Florida campus of The Scripps Research Institute (TSRI) have shed new light on these complex processes, showing that a particular protein plays a far more sophisticated role in neuron development than previously thought.
The study, published in the journal PLOS Genetics, focuses on the large, intracellular signaling protein RPM-1 that is expressed in the nervous system. TSRI Assistant Professor Brock Grill and his team show the surprising degree to which RPM-1 harnesses sophisticated mechanisms to regulate neuron development.
Specifically, the research sheds light on the role of RPM-1 in the development of axons or nerve fibers—the elongated projections of nerve cells that transmit electrical impulses away from the neuron via synapses. Some axons are quite long; in the sciatic nerve, axons run from the base of the spine to the big toe.
“Collectively, our recent work offers significant evidence that RPM-1 coordinates how long an axon grows with construction of synaptic connections,” said Grill. “Understanding how these two developmental processes are coordinated at the molecular level is extremely challenging. We’ve now made significant progress.”
Putting Together the Pieces
The study describes how RPM-1 regulates the activity of a single protein known as DLK-1, a protein that regulates neuron development and plays an essential role in axon regeneration. RPM-1 uses PPM-2, an enzyme that removes a phosphate group from a protein thereby altering its function, in combination with intrinsic ubiquitin ligase activity to directly inhibit DLK-1.
“Studies on RPM-1 have been critical to understanding how this conserved family of proteins works,” said Scott T. Baker, the first author of the study and a member of Grill’s research team. “Because RPM-1 plays multiple roles during neuronal development, you wouldn’t want to interfere with it. But exploring the role of PPM-2 in controlling DLK-1 and axon regeneration could be worthwhile—and could have implications in neurodegenerative diseases.”
The Grill lab has also explored other aspects of how RPM-1 regulates neuron development. A related study, also published in PLOS Genetics, shows that RPM-1 functions as a part of a novel pathway to control β-catenin activity—this is the first evidence that RPM-1 works in connection with extracellular signals, such as a family of protein growth factors known as Wnts, and is part of larger signaling networks that regulate development. A paper in the journal Neural Development shows that RPM-1 is localized at both the synapse and the mature axon tip, evidence that RPM-1 is positioned to potentially coordinate the construction of synapses with regulation of axon extension and termination.
(Source: scripps.edu)
Gene Found To Be Crucial For Formation Of Certain Brain Circuitry
Using a powerful gene-hunting technique for the first time in mammalian brain cells, researchers at Johns Hopkins report they have identified a gene involved in building the circuitry that relays signals through the brain. The gene is a likely player in the aging process in the brain, the researchers say. Additionally, in demonstrating the usefulness of the new method, the discovery paves the way for faster progress toward identifying genes involved in complex mental illnesses such as autism and schizophrenia — as well as potential drugs for such conditions. A summary of the study appears in the Dec. 12 issue of Cell Reports.
(Image: A mouse neuron with synapses shown: Red dots mark excitatory synapses, while green dots mark so-called inhibitory synapses. Credit: Kamal Sharma/Johns Hopkins University School of Medicine)
“We have been looking for a way to sift through large numbers of genes at the same time to see whether they affect processes we’re interested in,” says Richard Huganir, Ph.D., director of the Johns Hopkins University Solomon H. Snyder Department of Neuroscience and a Howard Hughes Medical Institute investigator, who led the study. “By adapting an automated process to neurons, we were able to go through 800 genes to find one needed for forming synapses — connections — among those cells.”
Although automated gene-sifting techniques have been used in other areas of biology, Huganir notes, many neuroscience studies instead build on existing knowledge to form a hypothesis about an individual gene’s role in the brain. Traditionally, researchers then disable or “knock out” the gene in lab-grown cells or animals to test their hypothesis, a time-consuming and laborious process.
In this study, Huganir’s group worked to test many genes all at once using plastic plates with dozens of small wells. A robot was used to add precise allotments of cells and nutrients to each well, along with molecules designed to knock out one of the cells’ genes — a different one for each well.
“The big challenge was getting the neurons, which are very sensitive, to function under these automated conditions,” says Kamal Sharma, Ph.D., a research associate in Huganir’s group. The team used a trial-and-error approach, adjusting how often the nutrient solution was changed and adding a washing step, and eventually coaxed the cells to thrive in the wells. In addition, Sharma says, they fine-tuned an automated microscope used to take pictures of the circuitry that had formed in the wells and calculated the numbers of synapses formed among the cells.
The team screened 800 genes in this way and found big differences in the well of cells with a gene called LRP6 knocked out. LRP6 had previously been identified as a player in a biochemical chain of events known as the Wnt pathway, which controls a range of processes in the brain. Interestingly, Sharma says, the team found that LRP6 was only found on a specific kind of synapse known as an excitatory synapse, suggesting that it enables the Wnt pathway to tailor its effects to just one synapse type.
“Changes in excitatory synapses are associated with aging, and changes in the Wnt pathway in later life may accelerate aging in general. However, we do not know what changes take place in the synaptic landscape of the aging brain. Our findings raise intriguing questions: Is the Wnt pathway changing that landscape, and if so, how?” says Sharma. “We’re interested in learning more about what other proteins LRP6 interacts with, as well as how it acts in different types of brain cells at different developmental stages of circuit development and refinement.”
Another likely outcome of the study is wider use of the gene-sifting technique, he says, to explore the genetics of complex mental illnesses. The automated method could also be used to easily test the effects on brain cells of a range of molecules and see which might be drug candidates.
New Theory of Synapse Formation in the Brain
The human brain keeps changing throughout a person’s lifetime. New connections are continually created while synapses that are no longer in use degenerate. To date, little is known about the mechanisms behind these processes. Jülich neuroinformatician Dr. Markus Butz has now been able to ascribe the formation of new neural networks in the visual cortex to a simple homeostatic rule that is also the basis of many other self-regulating processes in nature. With this explanation, he and his colleague Dr. Arjen van Ooyen from Amsterdam also provide a new theory on the plasticity of the brain – and a novel approach to understanding learning processes and treating brain injuries and diseases.
The brains of adult humans are by no means hard wired. Scientists have repeatedly established this fact over the last few years using different imaging techniques. This so-called neuroplasticity not only plays a key role in learning processes, it also enables the brain to recover from injuries and compensate for the loss of functions. Researchers only recently found out that even in the adult brain, not only do existing synapses adapt to new circumstances, but new connections are constantly formed and reorganized. However, it was not yet known how these natural rearrangement processes are controlled in the brain. In the open-access journal PLOS Computational Biology, Butz and van Ooyen now present a simple rule that explains how these new networks of neurons are formed.
"It’s very likely that the structural plasticity of the brain is the basis for long-term memory formation," says Markus Butz, who has been working at the recently established Simulation Laboratory Neuroscience at the Jülich Supercomputing Centre for the past few months. "And it’s not just about learning. Following the amputation of extremities, brain injury, the onset of neurodegenerative diseases, and strokes, huge numbers of new synapses are formed in order to adapt the brain to the lasting changes in the patterns of incoming stimuli."
Activity regulates synapse formation
Τhese results show that the formation of new synapses is driven by the tendency of neurons to maintain a ‘pre-set’ electrical activity level. If the average electric activity falls below a certain threshold, the neurons begin to actively build new contact points. These are the basis for new synapses that deliver additional input – the neuron firing rate increases. This also works the other way round: as soon as the activity level exceeds an upper limit, the number of synaptic connections is reduced to prevent any overexcitation – the neuron firing rate falls. Similar forms of homeostasis frequently occur in nature, for example in the regulation of body temperature and blood sugar levels.
However, Markus Butz stresses that this does not work without a certain minimal excitation of the neurons: “A neuron that no longer receives any stimuli loses even more synapses and will die off after some time. We must take this restriction into account if we want the results of our simulations to agree with observations.” Using the visual cortex as an example, the neuroscientists have studied the principles according to which neurons form new connections and abandon existing synapses. In this region of the brain, about 10% of the synapses are continuously regenerated. When the retina is damaged, this percentage increases even further. Using computer simulations, the authors succeeded in reconstructing the reorganization of the neurons in a way that conforms to experimental results from the visual cortex of mice and monkeys with damaged retinas.
The visual cortex is particularly suitable for demonstrating the new growth rule, because it has a property referred to as retinotopy: This means that points projected beside each other onto the retina are also arranged beside each other when they are projected onto the visual cortex, just like on a map. If areas of the retina are damaged, the cells onto which the associated images are projected receive different inputs. “In our simulations, you can see that areas which no longer receive any input from the retina start to build crosslinks, which allow them to receive more signals from their neighbouring cells,” says Markus Butz. These crosslinks are formed slowly from the edge of the damaged area towards the centre, in a process resembling the healing of a wound, until the original activity level is more or less restored.
Synaptic and structural plasticity
"The new growth rule provides structural plasticity with a principle that is almost as simple as that of synaptic plasticity," says co-author Arjen van Ooyen, who has been working on models for the development of neural networks for decades. As early as 1949, psychology professor Donald Olding Hebb discovered that connections between neurons that are frequently activated will become stronger. Those that exchange little information will become weaker. Today, many scientists believe that this Hebbian principle plays a central role in learning and memory processes. While synaptic plasticity in involved primarily in short-term processes that take from a few milliseconds to several hours, structural plasticity extends over longer time scales, from several days to months.
Structural plasticity therefore plays a particularly important part during the (early) rehabilitation phase of patients affected by neurological diseases, which also lasts for weeks and months. The vision driving the project is that valuable ideas for the treatment of stroke patients could result from accurate predictions of synapse formation. If doctors knew how the brain structure of a patient will change and reorganize during treatment, they could determine the ideal times for phases of stimulation and rest, thus improving treatment efficiency.
New approach for numerous applications
"It was previously assumed that structural plasticity also follows the principle of Hebbian plasticity. The findings suggest that structural plasticity is governed by the homeostatic principle instead, which was not taken into consideration before," says Prof. Abigail Morrison, head of the Simulation Laboratory Neuroscience at Jülich. Her team is already integrating the new rule into the freely accessible simulation software NEST, which is used by numerous scientists worldwide.
These findings are also of relevance for the Human Brain Project. Neuroscientists, medical scientists, computer scientists, physicists, and mathematicians in Europe are working hand in hand to simulate the entire human brain on high-performance computers of the next generation in order to better understand how it functions. “Due to the complex synaptic circuitry in the human brain, it’s not plausible that its fault tolerance and flexibility are achieved based on static connection rules. Models are therefore required for a self-organization process,” says Prof. Markus Diesmann from Jülich’s Institute of Neuroscience and Medicine, who is involved in the project. He heads Computational and Systems Neuroscience (INM-6), a subinstitute working at the interface between neuroscientific research and simulation technology.
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)
Multiple Contacts Are Key to Synapse Formation
Multiple synaptic contacts between nerve cells facilitate the creation of a new contact, as neuroscientists from the Bernstein Center Freiburg and the Forschungszentrum Jülich report in the latest issue of the journal PLoS Computational Biology. An integral mechanism of memory foundation is the formation of additional contacts between neurons in the brain. However, until now it was not known what conditions lead to the development of such synapses and how they are stabilized once created. By studying mathematical models, the scientists found a simple explanation for how and when synapses form – or disappear – in the brain.