Posts tagged homeostatic plasticity
Articles and news from the latest research reports.
Researchers Uncover an Unexpected Role for Endostatin in the Nervous System
Researchers at UC San Francisco have discovered that endostatin, a protein that once aroused intense interest as a possible cancer treatment, plays a key role in the stable functioning of the nervous system.
A substance that occurs naturally in the body, endostatin potently blocks the formation of new blood vessels. In studies in mice in the late 1990s, endostatin treatment virtually eliminated cancer by shutting down the blood supply to tumors, but subsequent human clinical trials proved disappointing.
“It was a very big surprise” to find that endostatin, through some other mechanism, helps to maintain the proper workings of synapses, the sites where communication between nerve cells takes place, said Graeme W. Davis, PhD, Hertzstein Distinguished Professor of Medicine in the Department of Biochemistry and Biophysics at UCSF and senior author of the new study. “Endostatin was not on our radar.”
The findings were reported online July 24 in the journal Neuron.
Synapses are continually shaped and reshaped by experience, a phenomenon known as plasticity. But for those changes to be meaningful, said Davis, they must take place against a stable background, which paradoxically requires another form of change that he and colleagues call “homeostatic plasticity.” Just as we change our pace, slowing down or speeding up, to keep abreast of a running partner, neurons adjust aspects of their function at synapses to compensate for changes in their synaptic partners brought on by aging, illness, or other factors.
In an example of homeostatic plasticity, in the neuromuscular disease myasthenia gravis, as muscle cells become less responsive to the neurotransmitter acetylcholine, nerve cells ramp up their secretion of the neurotransmitter to keep the system in balance for as long as possible. Some researchers believe that in other disorders, including autism and schizophrenia, a failure in such homeostatic mechanisms keeps synapses from functioning properly.
In previous research Davis noticed that applying a toxin to a muscle cell in the fruit fly Drosophila melanogaster triggers homeostatic plasticity in the neuron that forms a synapse on that muscle cell: the neuron—which is called presynaptic, because it is “before” the synapse with the muscle cell—reliably releases more neurotransmitter, just as happens when muscle cells begin to malfunction in myasthenia gravis.
Davis has since built on this model of homeostatic plasticity by painstakingly knocking out Drosophila genes one by one and recording from presynaptic neurons to see which genes are necessary for the homeostatic response, because it is these genes that may be compromised in diseases affecting the process.
“So far we’ve tested about 1,000 genes this way, which has entailed close to 10,000 recordings,” Davis said.
Using this technique Davis and colleagues observed at one point that knocking out a gene called multiplexin significantly hampered homeostatic plasticity in presynaptic neurons. But because that gene helps to form a structural protein known as collagen—which in humans is a component of ligaments, tendons, and cartilage—the finding wasn’t immediately considered relevant to synaptic function.
The team learned that the multiplexin protein can be snipped by an enzyme to produce endostatin, so in experiments led by postdoctoral fellow Tingting Wang, PhD, they tested whether endostatin might play a role in homeostatic plasticity.
“Nobody picked up multiplexin to work on for a couple of years, because we didn’t think a collagen could be that interesting,” Davis said. “Then, when a new postdoc, Tingting Wang, came to the lab, we started thinking about it harder.”
When the group genetically deleted the portion of Drosophila multiplexin that forms endostatin, presynaptic neurons behaved normally, but homeostatic plasticity was severely compromised when toxin was applied to postsynaptic muscle cells. On the opposite side of the coin, when the team overexpressed endostatin at Drosophila synapses lacking multiplexin, homeostasis was restored, whether endostatin was expressed in muscle cells or presynaptic neurons.
The research team is unsure precisely how and where endostatin exerts its effects on homeostatic plasticity, but they believe that multiplexin is cleaved at the postsynaptic site to form endostatin, and that the endostatin signal is conveyed to the presynaptic neuron to alter its function. “Because so many people in the cancer world have studied endostatin, there is a great set of tools available” to study the protein, Davis said, so he expects his group to make rapid progress in addressing these questions.
“Despite its checkered history in cancer, we know endostatin is a signaling molecule and we know that the brain has a great deal of collagen—we just haven’t known what it does, and we certainly don’t know what endostatin’s receptors in the brain might be.” Davis said. “But it’s pretty exciting to think about a new signaling molecule with a profound role in the stabilization of the function of neural circuits.”
(Source: ucsf.edu)
When neurons have less to say, they say it with particular emphasis
The brain is an extremely adaptable organ – but it is also very conservative according to scientists from the Max Planck Institute of Neurobiology in Martinsried in collaboration with colleagues from the Friedrich Miescher Institute in Basel and the Ruhr Institute Bochum. The researchers succeeded in demonstrating that neurons in the brain regulate their own excitability so that the activity level in the network remains as constant as possible. Even in the event of major changes, for example the complete absence of information from a sensory organ, the almost silenced neurons re-establish levels of activity similar to their previous ones after only 48 hours. The mean activity level thus achieved is a basic prerequisite for a healthy brain and the formation of new connections between neurons – an essential capacity for regeneration following injury to the brain or a sensory organ, for example.
Neurons communicate using electrical signals. They transmit these signals to neighbouring cells via special contact points known as the synapses. When a new item of information presents for processing, the cells can develop new synaptic contacts with their neighbouring cells or strengthen existing ones. To enable forgetting, these processes are also reversible. The brain is consequently in a constant state of reorganisation, through which individual neurons are prevented from becoming either too active or too inactive. The aim is to keep the level of activity constant, as the long-term overexcitement of neurons can result in damage to the brain.
Too little activity is not good either. “The cells can only re-establish connections with their neighbours when they are ‘awake’, so to speak, that is when they display a minimum level of activity,” explains Mark Hübener, head of the recently published study. The international team of researchers succeeded in demonstrating for the first time that the brain itself compensates for massive changes in neuronal activity within a period of two days, and can return to a similar level of activity to that before the change.
Up to now, the only indication of this astonishing capacity of the brain came from cell cultures. It was also unclear as to how neurons could control their own excitability in relation to the activity of the entire network. Now, the scientists have made significant progress towards finding an answer to this question. In their study, they examined the visual cortex of mice that recently went blind. As expected, but never previously demonstrated, the activity of the neurons in this area of the brain did not fall to zero but to half of the original value. “That alone was an astonishing finding, as it shows the extent to which the visual cortex also processes information from other areas of the brain,” explains Tobias Bonhoeffer, who has been researching processes in the visual cortex at his department in the Max Planck Institute of Neurobiology for many years. “However, things really became exciting when we observed the area further over the following hours and days.”
The scientists were able, under the microscope, to witness “live” how the neurons in the visual cortex became active again. After just a few hours, they could clearly observe how the points of contact between the affected cells and neighbouring cells increased in size. When synapses get bigger, they also become stronger and signals are transmitted faster and more effectively. As a result of this intensification of the contact between the neurons, the activity of the affected network returned to its starting value after a period of between 24 and 48 hours. “To put it simply, due to the absence of visual input, the cells had less to say – but when they did say something, they said it with particular emphasis,” explains Mark Hübener.
Due to the simultaneous strengthening of all of the synapses of the affected neurons, major reductions in the neuronal activity can be normalised again with surprising speed. The relatively stable activity level thereby achieved is an essential prerequisite for maintaining a healthy, adaptable brain.