(Image caption: In Greek mythology, Clotho – the eponym for the anti-aging factor klotho – is the Fate who spins the thread of life. Here, the goddess spins the metaphorical thread of life that is DNA, influencing lifespan and cognition. Illustration by Michael Griffin Kelley)

Better Cognition Seen with Gene Variant Carried by 1 in 5 People

A scientific team led by the Gladstone Institutes and UC San Francisco has discovered that a common form of a gene already associated with long life also improves learning and memory, a finding that could have implications for treating age-related diseases like Alzheimer’s.

The researchers found that people who carry a single copy of the KL-VS variant of the KLOTHO gene perform better on a wide variety of cognitive tests. When the researchers modeled the effects in mice, they found it strengthened the connections between neurons that make learning possible – what is known as synaptic plasticity – by increasing the action of a cell receptor critical to forming memories.

The discovery is a major step toward understanding how genes improve cognitive ability and could open a new route to treating diseases like Alzheimer’s. Researchers have long suspected that some people may be protected from the disease because of their greater cognitive capacity, or reserve. Since elevated levels of the klotho protein appear to improve cognition throughout the lifespan, raising klotho levels could build cognitive reserve as a bulwark against the disease.

“As the world’s population ages, cognitive frailty is our biggest biomedical challenge,” said Dena Dubal, MD, PhD, assistant professor of neurology, the David A. Coulter Endowed Chair in Aging and Neurodegeneration at UCSF and lead author of the study, published May 8 in Cell Reports. “If we can understand how to enhance brain function, it would have a huge impact on people’s lives.”

First to Link Between Klotho Variant and Better Cognition

Klotho was discovered in 1997 and named after the Fate from Greek mythology who spins the thread of life.

The investigators found that people who carry a single copy of the KL-VS variant of the KLOTHO gene, roughly 20 percent of the population, have more klotho protein in their blood than non-carriers. Besides increasing the secretion of klotho, the KL-VS variant may also change the action of the protein and is known to lessen age-related cardiovascular disease and promote longevity.

The team’s report is the first to link the KL-VS variant, or allele, to better cognition in humans, and buttresses these findings with genetic, electrophysiological, biochemical and behavioral experiments in mice.

The researchers tested the associations between the allele and age-related human cognition in three separate studies involving more than 700 people without dementia between the ages of 52 and 85. Altogether, it took about three years to conduct the work.

“These surprising results pave a promising new avenue of research,” said Roderick Corriveau, PhD, program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS). “Although preliminary, they suggest klotho could be used to bump up cognition for people suffering from dementia.”

Learning Better at All Stages of Life

Having the KL-VS allele did not seem to protect people from age-related cognitive decline. But overall the effect was to boost cognition, so that the middle-aged study participants began their decline from a higher point.

“Based on what was known about klotho, we expected it to affect the brain by changing the aging process,” said senior author Lennart Mucke, MD, who directs neurological research at the Gladstone Institutes and is a professor of neurology and the Joseph B. Martin Distinguished Professor of Neuroscience at UCSF. “But this is not what we found, which suggested to us that we were on to something new and different.”

To get a closer look at how the gene variant operates, the researchers used mice that were engineered to produce more of the mouse version of klotho and found that these mice learned better at all stages of life. Put through mazes, these transgenic mice were more likely to try different routes, an indication that they had superior working memory. In a test of spatial learning and memory, the mice with extra klothoperformed twice as well.

Researchers then analyzed the mouse brain tissue and found that the mice with elevated klotho had twice as many GluN2B subunits within synaptic connections. GluN2B is part of the N-methyl-D-aspartate receptor, or NMDAR, a key receptor involved in synaptic plasticity.

The researchers found more GluN2B-containing receptors in the hippocampus and frontal cortex, brain regions that support cognitive functions. When the researchers gave the mice a drug that blocks the action of these receptors, the klotho-enhanced mice lost their cognitive advantage.

(Image caption: During the learning processes, extensions grow on neurons. Synapses are located at the end of these extensions (left: as seen in nature; right: reconstruction). When the synapse growth is based on the correlated development of all synaptic components, it can remain stable for long periods of time. Credit: © MPI of Neurobiology/ Meyer)

Synapses – stability in transformation

Nothing lasts forever. This principle also applies to the proteins that make up the points of contact between our neurons. It is due to these proteins that the information arriving at a synapse can be transmitted and then received by the next neuron. When we learn something, new synapses are created or existing ones are strengthened. To enable us to retain long-term memories, synapses must remain stable for long periods of time, up to an entire lifetime. Researchers at the Max Planck Institute of Neurobiology in Martinsried near Munich have found an explanation as to how a synapse achieves remaining stable for a long time despite the fact that its proteins must be renewed regularly.

Learning in the laboratory

“We were interested first of all in what happens to the different components of a synapse when it grows during a learning process,” explains study leader Volker Scheuss. An understanding of how the components grow could also provide information about the long-term stability of synapses. Hence, the researchers studied the growth of synapses in tissue culture dishes following exposure to a (learning) stimulus. To do this, they deliberately activated individual synapses using the neurotransmitter glutamate: scientists have long known that glutamate plays an important role in learning processes and stimulates the growth of synapses. Over the following hours, the researchers observed the stimulated synapses and control synapses under a 2-photon microscope. To confirm the observed effects, they then examined individual synapses with the help of an electron microscope. “When you consider that individual synapses are only around one thousandth of a millimetre in size, this was quite a Sisyphean task,” says Tobias Bonhoeffer, the Director of the department where the research was carried out.

Synaptic stability – a concerted effort

The scientists discovered that during synapse growth the different protein structures always grew coordinated with each other. If one structural component was enlarged alone, or in a way that was not correctly correlated with the other components, its structural change would collapse soon after. Synapses with such incomplete changes cannot store any long-term memories.

The study findings show that the order and interaction between synaptic components is finely tuned and correlated. “In a system of this kind, it should be entirely possible to replace individual proteins while the rest of the structure maintains its integrity,” says Scheuss. However, if an entire group of components breaks away, the synapse is destabilised. This is also an important process given that the brain could not function correctly without the capacity to forget things. Hence, the study’s results provide not only important insight into the functioning and structure of synapses, they also establish a basis for a better understanding of memory loss, for example in the case of degenerative brain diseases.

(Image caption: Blockade of p25 generation in the brain of an Alzheimer’s disease mouse model mitigates amyloid plaque buildup. Hippocampal slices from a seven-month-old 5XFAD mouse (left) or 5XFAD;p35KI mouse (right), alongside markers for Aβ (red) and activated astrocyte (green). Nuclei are shown in blue.)

Neuroscientists find that limiting a certain protein in the brain reverses Alzheimer’s symptoms in mice

Limiting a certain protein in the brain reverses Alzheimer’s symptoms in mice, report neuroscientists at MIT’s Picower Intitute for Learning and Memory.

Researchers found that the overproduction of the protein known as p25 may be the culprit behind the sticky protein-fragment clusters that build up in the brains of Alzheimer’s patients. The work, which was published in the April 10 issue of Cell, could provide a new drug target for the treatment of the disease that affects more than five million Americans, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and senior author of the paper.

Abnormal clusters of protein fragments, known as beta amyloid plaques, are believed to cause the cognitive impairments, cell death, and tissue loss associated with Alzheimer’s. The p25 protein had been tied to the creation and buildup of beta amyloids, but until now, p25’s role in Alzheimer’s pathology was not well understood.

“This protein appears to help maintain normal brain activity, but also is part of a feedback loop with beta amyloids. It generates the plaques which, in turn, boost levels of p25,” Tsai says.

Lead author of the paper is Jinsoo Seo, a postdoc associate at the Picower Institute.

The benefits of p25 generation

Elevated p25 levels in the brain have been documented upon exposure to neurotoxic stimuli such as oxidative stress and beta amyloids.

“In this study, for the first time we show that a variety of physiological neuronal activities generate p25 in the hippocampus, where memories are encoded in the brain,” Tsai says.

To delineate the precise roles of p25, Tsai’s lab generated a transgenic mouse model, which enabled researchers to prevent the production of p25 without altering other proteins with essential roles in brain development.

The researchers found that p25 is required for synaptic plasticity, the ability of brain connections to change over time; especially for the process called long-term depression (LTD) that selectively weakens sets of synapses and is associated with memory extinction.

Tsai’s team observed that the mice unable to generate p25 could learn new tasks and form memories normally; however, when the researchers began to address memory extinction, they soon noticed that the mice have difficulties with replacing older memories with newer ones.

Too much of a good thing

“This finding not only boosts our understanding of p25 in synaptic functions, but also explains the underlying mechanism of the inordinate synaptic depression observed in the Alzheimer’s brain,” Seo says.

“This finding led us to question whether the blockade of p25 generation could mitigate pathological phenotypes in the Alzheimer’s brain,” Tsai says.

In the mouse model of Alzheimer’s disease, inhibiting p25 production improved cognitive function, greatly reduced plaque formation and neuroinflammation, hallmark features of Alzheimer’s disease.

These results hold out the hope that a drug that regulates p25 could benefit Alzheimer’s disease patients by improving cognitive function and perhaps delaying the development of brain pathology, Tsai says.

Lack of coronin 1 protein causes learning deficits and aggressive behavior

Learning and memory relies on the proper processing of signals that stimulate neuronal cells within the brain. Researchers at the Biozentrum of the University of Basel, together with an international team of scientists, has uncovered an important role for the protein coronin 1 in cognition and behavior. They found that a lack of coronin 1 in mouse and in man is associated with poor memory, defective learning and aggressive behavior. The results, recently published in PLOS Biology, identify a novel risk factor for neurobehavioral dysfunction and reveal a molecular pathway involved in transferring information within neurons.

Organisms must be able to sense signals from the outside and translate these into biochemical cues in order to adequately respond to their environment. This capability is also required to process information that reaches the brain. Within the brain, stimulation of neurons activates genes that are required, for example for learning and memory. In collaboration with an international and interdisciplinary team the research group led by Prof. Jean Pieters from the Biozentrum, University of Basel, has now uncovered the role of an evolutionarily conserved protein, called coronin 1, in providing a link between the extracellular stimulus and neuronal activation that ultimately results in efficient learning and memory in both mice and men.

From the immune system to the brain
In earlier work, Pieters’ team discovered the protein coronin 1 as being essential for the proper transduction of signals in immune cells. In mice lacking coronin 1 the researchers further investigated the molecular mechanism. Surprisingly, these mice showed aberrant behavior. In particular, mice lacking coronin 1 appeared to be far more aggressive and display extreme grooming activity, an indication of reduced sociability. An in-depth analysis in collaboration with scientists from the Friedrich Miescher Institute in Basel and the University of Bordeaux unveiled profound learning and behavioral problems and severe defects in the ability to activate neurons in the absence of coronin 1.

Activation of a signaling cascade
But how does coronin 1 ensure proper neurobehavioral functioning? Normally, stimulation of the cell surface results in an activation of an intracellular cascade of reactions and ultimately stimulates the production of the signaling molecule cAMP which then activates a number of processes, including the transcription of gene involved in neurobehavior. “We found that in the absence of coronin 1, cell surface stimulation leads to a defective cAMP production”, explains Pieters. “This in turn affects the signal transduction which is finally responsible for the deficits in learning and memory formation.”

Of mice and men
Furthermore, the researchers analyzed the clinical history of a patient lacking coronin 1 due to a mutation: it turned out that this patient showed learning defects and aggressive behavior. With this study, Pieters and his project collaborators not only define a crucial role for coronin 1 in cognition and behavior, but also unravel a coronin 1-dependent signaling pathway that may be explored both for potential risk factors as well as future interventions to modulate neurobehavioral dysfunction.

New ideas change your brain cells

A new University of British Columbia study identifies an important molecular change that occurs in the brain when we learn and remember.

Published this month in Nature Neuroscience, the research shows that learning stimulates our brain cells in a manner that causes a small fatty acid to attach to delta-catenin, a protein in the brain. This biochemical modification is essential in producing the changes in brain cell connectivity associated with learning, the study finds.

In animal models, the scientists found almost twice the amount of modified delta-catenin in the brain after learning about new environments. While delta-catenin has previously been linked to learning, this study is the first to describe the protein’s role in the molecular mechanism behind memory formation.

“More work is needed, but this discovery gives us a much better understanding of the tools our brains use to learn and remember, and provides insight into how these processes become disrupted in neurological diseases,” says co-author Shernaz Bamji, an associate professor in UBC’s Life Sciences Institute.

It may also provide an explanation for some mental disabilities, the researchers say. People born without the gene have a severe form of mental retardation called Cri-du-chat syndrome, a rare genetic disorder named for the high-pitched cat-like cry of affected infants. Disruption of the delta-catenin gene has also been observed in some patients with schizophrenia.

“Brain activity can change both the structure of this protein, as well as its function,” says Stefano Brigidi, first author of the article and a PhD candidate Bamji’s laboratory. “When we introduced a mutation that blocked the biochemical modification that occurs in healthy subjects, we abolished the structural changes in brain’s cells that are known to be important for memory formation.”

Background

According to the researchers, more work is needed to fully establish the importance of delta-catenin in building the brain connectivity behind learning and memory. Disruptions to these nerve cell connections are also believed to cause neurodegenerative diseases such as Alzheimer’s and Huntington disease. Understanding the biochemical processes that are important for maintaining these connections may help address the abnormalities in nerve cells that occur in these disease states.

(Image: Shutterstock)

Scientists discover a new pathway for fear deep within the brain

Fear is primal. In the wild, it serves as a protective mechanism, allowing animals to avoid predators or other perceived threats. For humans, fear is much more complex. A normal amount keeps us safe from danger. But in extreme cases, like post-traumatic stress disorder (PTSD), too much fear can prevent people from living healthy, productive lives. Researchers are actively working to understand how the brain translates fear into action. Today, scientists at Cold Spring Harbor Laboratory (CSHL) announce the discovery of a new neural circuit in the brain that directly links the site of fear memory with an area of the brainstem that controls behavior.

How does the brain convert an emotion into a behavioral response? For years, researchers have known that fear memories are learned and stored in a small structure in the brain known as the amygdala. Any disturbing event activates neurons in the lateral and then central portions of the amygdala. The signals are then communicated internally, passing from one group of neurons to the next. From there, they reach neurons in the brainstem, the action center for fear responses.

Last year, CSHL Associate Professor Bo Li and his colleagues were able to use new genetic techniques to determine the precise neurons in the central amygdala that control fear memory. His current research exploits new methods to understand how the central amygdala communicates fear memories to the areas of the brain that are responsible for action.

In work published today in The Journal of Neuroscience, Li and his team identify a group of long-range neurons that extend from the central amygdala. These neurons project to an area of the brainstem, known as the midbrain periaqueductal gray (PAG), that controls the fear response.

Li and his colleagues explored how these long-range neurons participate in fear conditioning. They trained animals to associate a particular sound with a shock, conditioning the animals to fear the sound. In these animals, the activity of the long-range projection neurons in the central amygdala became enhanced.

“This study not only establishes a novel pathway for fear learning, but also identifies neurons that actively participate in fear conditioning,” says Li. “This new pathway can mediate the effect of the central amygdala directly, rather than signaling through other neurons, as traditionally thought.”

The next step for these researchers is to apply this knowledge to models of PTSD. “We are working to find out how these circuits behave in anxiety disorders, so that we can hopefully learn to control fear in diseases such as PTSD,” says Li.

Brain process takes paper shape

A paper-based device that mimics the electrochemical signalling in the human brain has been created by a group of researchers from China.

The thin-film transistor (TFT) has been designed to replicate the junction between two neurons, known as a biological synapse, and could become a key component in the development of artificial neural networks, which could be utilised in a range of fields from robotics to computer processing.

The TFT, which has been presented today, 13 February, in IOP Publishing’s journal Nanotechnology, is the latest device to be fabricated on paper, making the electronics more flexible, cheaper to produce and environmentally friendly.

The artificial synaptic TFT consisted of indium zinc oxide (IZO), as both a channel and a gate electrode, separated by a 550-nanometre-thick film of nanogranular silicon dioxide electrolyte, which was fabricated using a process known as chemical vapour deposition.

The design was specific to that of a biological synapse—a small gap that exists between adjoining neurons over which chemical and electrical signals are passed. It is through these synapses that neurons are able to pass signals and messages around the brain.

All neurons are electrically excitable, and can generate a ‘spike’ when the neuron’s voltage changes by large enough amounts. These spikes cause signals to flow through the neurons which cause the first neuron to release chemicals, known as neurotransmitters, across the synapse, which are then received by the second neuron, passing the signal on.

Similar to these output spikes, the researchers applied a small voltage to the first electrode in their device which caused protons—acting as a neurotransmitter—from the silicon dioxide films to migrate towards the IZO channel opposite it.

As protons are positively charged, this caused negatively charged electrons to be attracted towards them in the IZO channel which subsequently allowed a current to flow through the channel, mimicking the passing on of a signal in a normal neuron.

As more and more neurotransmitters are passed across a synapse between two neurons in the brain, the connection between the two neurons becomes stronger and this forms the basis of how we learn and memorise things.

This phenomenon, known as synaptic plasticity, was demonstrated by the researchers in their own device. They found that when two short voltages were applied to the device in a short space of time, the second voltage was able to trigger a larger current in the IZO channel compared to the first applied voltage, as if it had ‘remembered’ the response from the first voltage.

Corresponding author of the study, Qing Wan, from the School of Electronic Science and Engineering, Nanjing University, said: ‘A paper-based synapse could be used to build lightweight and biologically friendly artificial neural networks, and, at the same time, with the advantages of flexibility and biocompatibility, could be used to create the perfect organism–machine interface for many biological applications.’

Sleep is the Price the Brain Pays for Learning

Why do animals ranging from fruit flies to humans all need to sleep? After all, sleep disconnects them from their environment, puts them at risk and keeps them from seeking food or mates for large parts of the day.

Two leading sleep scientists from the University of Wisconsin School of Medicine and Public Health say that their synaptic homeostasis hypothesis of sleep or “SHY” challenges the theory that sleep strengthens brain connections.

The SHY hypothesis, which takes into account years of evidence from human and animal studies, says that sleep is important because it weakens the connections among brain cells to save energy, avoid cellular stress, and maintain the ability of neurons to respond selectively to stimuli.

“Sleep is the price the brain must pay for learning and memory,” says Dr. Giulio Tononi, of the UW Center for Sleep and Consciousness. “During wake, learning strengthens the synaptic connections throughout the brain, increasing the need for energy and saturating the brain with new information. Sleep allows the brain to reset, helping integrate newly learned material with consolidated memories, so the brain can begin anew the next day.”

Tononi and his co-author Dr. Chiara Cirelli, both professors of psychiatry, explain their hypothesis in a review article in today’s issue of the journal Neuron. Their laboratory studies sleep and consciousness in animals ranging from fruit flies to humans; SHY takes into account evidence from molecular, electrophysiological and behavioral studies, as well as from computer simulations.”Synaptic homeostasis” refers to the brain’s ability to maintain a balance in the strength of connections within its nerve cells.

Why would the brain need to reset? Suppose someone spent the waking hours learning a new skill, such as riding a bike. The circuits involved in learning would be greatly strengthened, but the next day the brain will need to pay attention to learning a new task. Thus, those bike- riding circuits would need to be damped down so they don’t interfere with the new day’s learning.

“Sleep helps the brain renormalize synaptic strength based on a comprehensive sampling of its overall knowledge of the environment,” Tononi says, “rather than being biased by the particular inputs of a particular waking day.” 

The reason we don’t also forget how to ride a bike after a night’s sleep is because those active circuits are damped down less than those that weren’t actively involved in learning. Indeed, there is evidence that sleep enhances important features of memory, including acquisition, consolidation, gist extraction, integration and “smart forgetting,” which allows the brain to rid itself of the inevitable accumulation of unimportant details.

However, one common belief is that sleep helps memory by further strengthening the neural circuits during learning while awake. But Tononi and Cirelli believe that consolidation and integration of memories, as well as the restoration of the ability to learn, all come from the ability of sleep to decrease synaptic strength and enhance signal-to-noise ratios.

While the review finds testable evidence for the SHY hypothesis, it also points to open issues. One question is whether the brain could achieve synaptic homeostasis during wake, by having only some circuits engaged, and the rest off-line and thus resetting themselves.

Other areas for future research include the specific function of REM sleep (when most dreaming occurs) and the possibly crucial role of sleep during development, a time of intense learning and massive remodeling of brain.

Take note students: Mice that ‘cram’ for exams remember less

It’s been more than 100 years since German psychologist Hermann Ebbinghaus determined that learning interspersed with rest created longer-lasting memories than so-called cramming, or learning without rest intervals.

Common brain cell plays key role in shaping neural circuit

Stanford University School of Medicine neuroscientists have discovered a new role played by a common but mysterious class of brain cells.

Their findings, published online Nov. 24 in Nature, show that these cells, called astrocytes because of their star-like shape, actively refine nerve-cell circuits by selectively eliminating synapses — contact points through which nerve cells, or neurons, convey impulses to one another — much as a sculptor chisels away excess bits of rock to create an artwork.

“This was an entirely unknown function of astrocytes,” said Ben Barres, MD, PhD, professor and chair of neurobiology and the study’s senior author. The lead author was Won-Suk Chung, PhD, a postdoctoral scholar in Barres’ lab. More than one-third of all the cells in the human brain are astrocytes. But until quite recently, their role in the brain has remained obscure.

The study was performed on brain tissue from mice, but it is likely to apply to people as well, Barres said.

The discovery adds to a growing body of evidence that substantial remodeling of brain circuits takes place in the adult brain and that astrocytes are master sculptors of its constantly evolving synaptic architecture. The findings also raise the question of whether deficits and excesses in this astrocytic function could underlie, respectively, the loss of this remodeling capacity in old age or the wholesale destruction of synapses that erupts in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease.

“Astrocytes are in the driver’s seat when it comes to synapse formation, function and elimination,” Barres said. In previous studies, he and his colleagues have shown that astrocytes play a critical role in determining exactly where and when new synapses are generated.

The new study showed that astrocytes’ synapse-gobbling behavior persists into adulthood and is triggered by activity in the neurons, suggesting astrocytes may be central to the constant fine-tuning and reconfiguring of brain circuits occurring throughout our lives in response to experiences such as learning, recollection, emotion and motion. While a healthy brain’s neurons remain intact for much a person’s lifetime, the connections between them — the synapses — are constantly forming, strengthening, weakening or dying.

The Barres team also has previously implicated another brain cell type, collectively known as microglia, in synaptic pruning in early development, when the young brain undergoes ongoing episodes of circuit remodeling. The role of astrocytes in synaptic refining, the new study shows, differs from that of microglia both in timing and mechanism.

Barres’ team began to suspect astrocytes’ participation in the pruning process when, having developed methods for isolating exceptionally pure populations of different types of brain cells, they saw that the genes for two separate biochemical pathways were active in astrocytes. Both of these pathways are involved in phagocytosis, the trash-collection process by which specialized cells in the body engulf, ingest and digest dead cells; foreign materials, including bacteria; debris from wounds; and so forth. At the leading end of the two pathways were two phagocytic receptors, MERKTK and MEGF10, which in other cell types have been shown to bind to particular proteins on targeted cells or materials, triggering the ensuing engulfment, ingestion and digestion of the targets.

It’s known that much of an astrocyte’s surface membrane is typically in close contact with neurons. In fact, a single astrocyte may ensheathe thousands of synapses. It was only natural, Barres said, to wonder whether astrocytes play some role in eliminating synapses.

The researchers first demonstrated that both MERKTK and MEGF10, along with their entire tool kits of cooperating proteins, are present in living astrocytes in the mouse brain. (In unpublished work, they have since confirmed this using human astrocytes.) Next, they showed that mouse astrocytes in a lab dish eagerly gobbled up synapses and dispatched them to their lysosomes, highly acidic internal garbage disposals found in most cells in the body. But this engulfment was dependent on astrocytes having functional MEGF10 and MERTK. Disabling one or the other receptor’s function cut in half astrocytes’ ability to engorge themselves on synapses; knocking out both receptors lowered the synapse-eating activity by about 90 percent.

To see if this happens in real life, Chung, Barres and their associates turned to a familiar experimental model: a brain area called the lateral geniculate nucleus, which is a critical component of the brain’s vision-processing system. The LGN receives inputs from neurons just a couple of steps downstream from the photoreceptors in the retina. In early development, neurons in the LGN are innervated by inputs from both eyes. But at a critical point in development, a highly selective synaptic-pruning process kicks in, resulting in each neuron from one side of the LGN being contacted pretty much only by neurons from a single eye. This pruning process in the LGN is dependent on the transmission of waves of spontaneous neuronal impulses originating in the retina.

Experimenting with mice that had entered the critical period for synaptic pruning in the LGN, the investigators labeled the incoming neurons in this system with different-colored stains so their synaptic regions could be identified within astrocytes if the astrocytes ate them up. And sure enough, a lot of this label turned up inside astrocytes’ lysosomes, indicating that astrocytes were actively ingesting synapses. Knocking out one or another or, especially, both of the two phagocytic receptors greatly reduced the amount of labeled synaptic material found in astrocytes. Impairing astrocytic MERKTK and MEGF10 function also caused a failure of LGN neurons to restrict their inputs to only neurons from just one eye, clearly implicating astrocytes in that process. Electrophysiology experiments proved that the LGN neurons in the MERKTK- and MEGF10-knockout mice retained an excessive number of synapses, demonstrating that astrocytes play an active role in pruning synapses during development.

Importantly, injection of a drug blocking the transmission of spontaneous waves of electrical impulses originating in the retina severely impaired astrocytes’ ability to eat synapses, showing that the synapse-pruning propensity is linked to neuronal activity. Other tests showed that astrocytic phagocytosis of synapses continues into adulthood.

Barres said this raises the question of whether astrocytes function throughout life to continually restructure our neuronal circuitry in response to experientially induced brain activity. If astrocytes’ synaptic snacking slows with aging, as that of other phagocytic cell types is known to do, it could reduce the aging brain’s capacity to adapt to new experiences, he said. “Maybe you need the astrocytes to gobble up old synapses to make room for new ones.”

If so, it may be possible someday to design drugs to keep astrocytes’ phagocytic process from slowing, Barres added. Such drugs might prevent the accumulation in aging brains of past-their-prime synapses, which are vulnerable to degeneration in Alzheimer’s, Parkinson’s and other neurodegenerative disease characterized by massive synapse loss.

(Image credit)