31 Mart 2016 Perşembe
How the brain processes emotions
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Some mental illnesses may stem, in part, from the brain’s inability to correctly assign emotional associations to events. For example, people who are depressed often do not feel happy even when experiencing something that they normally enjoy.
A new study from MIT reveals how two populations of neurons in the brain contribute to this process. The researchers found that these neurons, located in an almond-sized region known as the amygdala, form parallel channels that carry information about pleasant or unpleasant events.
Learning more about how this information is routed and misrouted could shed light on mental illnesses including depression, addiction, anxiety, and posttraumatic stress disorder, says Kay Tye, the Whitehead Career Development Assistant Professor of Brain and Cognitive Sciences and a member of MIT’s Picower Institute for Learning and Memory.
“I think this project really cuts across specific categorizations of diseases and could be applicable to almost any mental illness,” says Tye, the senior author of the study, which appears in the March 31 online issue of Neuron.
The paper’s lead authors are postdoc Anna Beyeler and graduate student Praneeth Namburi.
Emotional circuits
In a previous study, Tye’s lab identified two populations of neurons involved in processing positive and negative emotions. One of these populations relays information to the nucleus accumbens, which plays a role in learning to seek rewarding experiences, while the other sends input to the centromedial amygdala.
In the new study, the researchers wanted to find out what those neurons actually do as an animal reacts to a frightening or pleasurable stimulus. To do that, they first tagged each population with a light-sensitive protein called channelrhodopsin. In three groups of mice, they labeled cells projecting to the nucleus accumbens, the centromedial amygdala, and a third population that connects to the ventral hippocampus. Tye’s lab has previously shown that the connection to the ventral hippocampus is involved in anxiety.
Tagging the neurons is necessary because the populations that project to different targets are otherwise indistinguishable. “As far as we can tell they’re heavily intermingled,” Tye says. “Unlike some other regions of the brain, there is no topographical separation based on where they go.”
After labeling each cell population, the researchers trained the mice to discriminate between two different sounds, one associated with a reward (sugar water) and the other associated with a bitter taste (quinine). They then recorded electrical activity from each group of neurons as the mice encountered the two stimuli. This technique allows scientists to compare the brain’s anatomy (which neurons are connected to each other) and its physiology (how those neurons respond to environmental input).
The researchers were surprised to find that neurons within each subpopulation did not all respond the same way. Some responded to one cue and some responded to the other, and some responded to both. Some neurons were excited by the cue while others were inhibited.
“The neurons within each projection are very heterogeneous. They don’t all do the same thing,” Tye says.
However, despite these differences, the researchers did find overall patterns for each population. Among the neurons that project to the nucleus accumbens, most were excited by the rewarding stimulus and did not respond to the aversive one. Among neurons that project to the central amygdala, most were excited by the aversive cue but not the rewarding cue. Among neurons that project to the ventral hippocampus, the neurons appeared to be more balanced between responding to the positive and negative cues.
“This is consistent with the previous paper, but we added the actual neural dynamics of the firing and the heterogeneity that was masked by the previous approach of optogenetic manipulation,” Tye says. “The missing piece of that story was what are these neurons actually doing, in real time, when the animal is being presented with stimuli.”
Digging deep
The findings suggest that to fully understand how the brain processes emotions, neuroscientists will have to delve deeper into more specific populations, Tye says.
“Five or 10 years ago, everything was all about specific brain regions. And then in the past four or five years there’s been more focus on specific projections. And now, this study presents a window into the next era, when even specific projections are not specific enough. There’s still heterogeneity even when you subdivide at this level,” she says. “We’ve still got a long way to go in terms of appreciating the full complexities of the brain.”
“Neuroscience is quickly moving beyond the classical idea of ‘one brain region equals one function,’” says Joshua Johansen, a team leader at the RIKEN Brain Science Institute in Japan, who was not involved in the research. “This paper represents an important step in this process by showing that within the amygdala, the way distinct populations of cells process information is a critical determinant of how emotional responses arise.”
Another question still remaining is why these different populations are intermingled in the amygdala. One hypothesis is that the cells responding to different inputs need to be able to quickly interact with each other, coordinating responses to an urgent signal, such as an alert that danger is present. “We are exploring the interactions between these different projections, and we think that could be a key to how we so quickly select an appropriate action when we’re presented with a stimulus,” Tye says.
In the long term, the researchers hope their work will lead to new therapies for mental illnesses. “The first step is to define the circuits and then try to go in animal models of these pathologies and see how these circuits are functioning differently. Then we can try to develop strategies to restore them and try to translate that to human patients,” says Beyeler, who is soon starting her own lab at the University of Lausanne to further pursue this line of research.
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Handheld surgical ‘pen’ prints human stem cells
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In a landmark proof-of-concept experiment, Australian researchers have used a handheld 3D printing pen to ‘draw’ human stem cells in freeform patterns with extremely high survival rates.
The device, developed out of collaboration between ARC Centre of Excellence for Electromaterials Science (ACES) researchers and orthopaedic surgeons at St Vincent’s Hospital, Melbourne, is designed to allow surgeons to sculpt customised cartilage implants during surgery.
Using a hydrogel bio-ink to carry and support living human stem cells, and a low powered light source to solidify the ink, the pen delivers a cell survival rate in excess of 97%.
3D bioprinters have the potential to revolutionise tissue engineering -they can be used to print cells, layer-by-layer, to build up artificial tissues for implantation.
But in some applications, such as cartilage repair, the exact geometry of an implant cannot be precisely known prior to surgery. This makes it extremely difficult to pre-prepare an artificial cartilage implant.
The Biopen special is held in the surgeon’s hands, allowing the surgeon unprecedented control in treating defects by filling them with bespoke scaffolds.
Professor Peter Choong, Director of Orthopaedics at St Vincent’s Hospital Melbourne, developed the concept with ACES Director Professor Gordon Wallace.
“The development of this type of technology is only possible with interactions between scientists and clinicians – clinicians to identify the problem and scientists to develop a solution,” Professor Choong said.
The team designed the BioPen with the practical constraints of surgery in mind and fabricated it using 3D printed medical grade plastic and titanium. The device is small, lightweight, ergonomic and sterilisable. A low powered light source is fixed to the device and solidifies the inks during dispensing.
“The biopen project highlights both the challenges and exciting opportunities in multidisciplinary research. When we get it right we can make extraordinary progress at a rapid rate,” Professor Wallace said.
The work was is published journal Biofabrication.
Design expertise and fabrication of the BioPen was supported by the Materials Node of the Australian National Fabrication Facility.
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30 Mart 2016 Çarşamba
Stem cells used to successfully regenerate damage in corticospinal injury
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Writing in the March 28, 2016 issue of Nature Medicine, researchers at University of California, San Diego School of Medicine and Veterans Affairs San Diego Healthcare System, with colleagues in Japan and Wisconsin, report that they have successfully directed stem cell-derived neurons to regenerate lost tissue in damaged corticospinal tracts of rats, resulting in functional benefit.
“The corticospinal projection is the most important motor system in humans,” said senior study author Mark Tuszynski, MD, PhD, professor in the UC San Diego School of Medicine Department of Neurosciences and director of the UC San Diego Translational Neuroscience Institute. “It has not been successfully regenerated before. Many have tried, many have failed — including us, in previous efforts.”
“The new thing here was that we used neural stem cells for the first time to determine whether they, unlike any other cell type tested, would support regeneration. And to our surprise, they did.”
Specifically, the researchers grafted multipotent neural progenitor cells into sites of spinal cord injury in rats. The stem cells were directed to specifically develop as a spinal cord, and they did so robustly, forming functional synapses that improved forelimb movements in the rats. The feat upends an existing belief that corticospinal neurons lacked internal mechanisms needed for regeneration.
Previous studies have reported functional recovery in rats following various therapies for spinal cord injury, but none had involved regeneration of corticospinal axons. In humans, the corticospinal tract extends from the cerebral cortex in the upper brain down into the spinal cord.
“We humans use corticospinal axons for voluntary movement,” said Tuszynski. “In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.”
Nonetheless, the road to testing and treatment in people remains long and uncertain.
“There is more work to do prior to moving to humans,” Tuszynski said. We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”
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Co-authors include Ken Kadoya, UC San Diego and Kokkaido University, Japan; Paul Lu, UC San Diego and VA San Diego Healthcare System; Kenny Nguyen, Corrine Lee-Kubli, Kumamaru Hiromi, Gunnar Poplawski, Jennifer Dulin, Yoshio Takashima, Jeremy Biane and James Conner, UC San Diego; Lin Yao, Joshua Knackert and Su-Chun Zhang, University of Wisconsin.
Funding for this research came, in part, from the Veterans Administration, the National Institutes of Health (grant NS09881), the Craig H. Neilsen Foundation, the Bernard and Anne Spitzer Charitable Trust, the D. Miriam and Sheldon Adelson Medical Research Foundation and Kitami Kobayashi Hospital.
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29 Mart 2016 Salı
26 Mart 2016 Cumartesi
How one gene contributes to two diseases
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Although it is known that psychiatric disorders have a strong genetic component, untangling the web of genes contributing to each disease is a daunting task. Scientists have found hundreds of genes that are mutated in patients with disorders such as autism, but each patient usually has only a handful of these variations.
To further complicate matters, some of these genes contribute to more than one disorder. One such gene, known as Shank3, has been linked to both autism and schizophrenia.
MIT neuroscientists have now shed some light on how a single gene can play a role in more than one disease. In a study appearing in the Dec. 10 online edition of Neuron, they revealed that two different mutations of the Shank3 gene produce some distinct molecular and behavioral effects in mice.
“This study gives a glimpse into the mechanism by which different mutations within the same gene can cause distinct defects in the brain, and may help to explain how they may contribute to different disorders,” says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience at MIT, a member of MIT’s McGovern Institute for Brain Research, a member of the Stanley Center for Psychiatric Research at the Broad Institute, and the senior author of the study.
The findings also suggest that identifying the brain circuits affected by mutated genes linked to psychiatric disease could help scientists develop more personalized treatments for patients in the future, Feng says.
The paper’s lead authors are McGovern Institute research scientist Yang Zhou, graduate students Tobias Kaiser and Xiangyu Zhang, and research affiliate Patricia Monteiro.
Disrupted communication
The protein encoded by Shank3 is found in synapses — the junctions between neurons that allow them to communicate with each other. Shank3 is a scaffold protein, meaning it helps to organize hundreds of other proteins clustered on the postsynaptic cell membrane, which are required to coordinate the cell’s response to signals from the presynaptic cell.
In 2011, Feng and colleagues showed that by deleting Shank3 in mice they could induce two of the most common traits of autism — avoidance of social interaction, and compulsive, repetitive behavior. A year earlier, researchers at the University of Montreal identified a Shank3 mutation in patients suffering from schizophrenia, which is characterized by hallucinations, cognitive impairment, and abnormal social behavior.
Feng wanted to find out how these two different mutations in the Shank3 gene could play a role in such different disorders. To do that, he and his colleagues engineered mice with each of the two mutations: The schizophrenia-related mutation results in a truncated version of the Shank3 protein, while the autism-linked mutation leads to a total loss of the Shank3 protein.
Behaviorally, the mice shared many defects, including strong anxiety. However, the mice with the autism mutation had very strong compulsive behavior, manifested by excessive grooming, which was rarely seen in mice with the schizophrenia mutation.
In the mice with the schizophrenia mutation, the researchers saw a type of behavior known as social dominance. These mice trimmed the whiskers and facial hair of the genetically normal mice sharing their cages, to an extreme extent. This is a typical way for mice to display their social dominance, Feng says.
By activating the mutations in different parts of the brain and at different stages of development, the researchers found that the two mutations affected brain circuits in different ways. The autism mutation exerted its effects early in development, primarily in a part of the brain known as the striatum, which is involved in coordinating motor planning, motivation, and habitual behavior. Feng believes that disruption of synapses in the striatum contributes to the compulsive behavior seen in those mice.
In mice carrying the schizophrenia-associated mutation, early development was normal, suggesting that truncated Shank3 can adequately fill in for the normal version during this stage. However, later in life, the truncated version of Shank3 interfered with synaptic functions and connections in the brain’s cortex, where executive functions such as thought and planning occur. This suggests that different segments of the protein — including the stretch that is missing in the schizophrenia-linked mutation — may be crucial for different roles, Feng says.
The new paper represents an important first step in understanding how different mutations in the same gene can lead to different diseases, says Joshua Gordon, an associate professor of psychiatry at Columbia University.
“The key is to identify how the different mutations alter brain function in different ways, as done here,” says Gordon, who was not involved in the research. “Autism strikes early in childhood, while schizophrenia typically arises in adolescence or early adulthood. The finding that the autism-associated mutation has effects at a younger age than the schizophrenia-associated mutation is particularly intriguing in this context.”
Modeling disease
Although only a small percentage of autism patients have mutations in Shank3, many other variant synaptic proteins have been associated with the disorder. Future studies should help to reveal more about the role of the many genes and mutations that contribute to autism and other disorders, Feng says. Shank3 alone has at least 40 identified mutations, he says.
“We cannot consider them all to be the same,” he says. “To really model these diseases, precisely mimicking each human mutation is critical.”
Understanding exactly how these mutations influence brain circuits should help researchers develop drugs that target those circuits and match them with the patients who would benefit most, Feng says, adding that a tremendous amount of work needs to be done to get to that point.
His lab is now investigating what happens in the earliest stages of the development of mice with the autism-related Shank3 mutation, and whether any of those effects can be reversed either during development or later in life.
The research was funded by the Simons Center for the Social Brain at MIT, the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, the Poitras Center for Affective Disorders Research at MIT, and National Institute of Mental Health.
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Protein imaging reveals detailed brain architecture
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MIT chemical engineers and neuroscientists have developed a new way to classify neurons by labeling and imaging the proteins found in each cell. This type of imaging offers clues to each neuron’s function and should help in mapping the human brain, the researchers say.
“Each cell uses a unique combination of proteins. It’s basically a fingerprint,” says Kwanghun Chung, who is the Samuel A. Goldblith Assistant Professor in the Department of Chemical Engineering, a member of MIT’s Institute for Medical Engineering and Science (IMES) and Picower Institute for Learning and Memory, and the leader of the research team. “If you can look at expression patterns of many proteins, then you can guess each cell’s type and what it’s doing.”
Using this approach, the researchers were able to visualize 22 different proteins inside human brain slices, but the method could be scaled to analyze many more proteins and larger tissue samples. This could help scientists learn more about how diseases alter brain chemistry.
“Now, researchers will be able to investigate the differences between brains from disease models and normal animals, simultaneously looking at potentially dozens of different molecules. This is very important, as the individual variation between brains would make it difficult to make solid connections when looking at those same molecules, one at a time, between dozens of samples,” says graduate student Evan Murray, one of the lead authors of a paper describing the technique in the Dec. 3 issue of Cell.
The paper’s other lead authors are graduate students Jae Hun Cho, Daniel Goodwin, and Justin Swaney, and postdoc Taeyun Ku.
Using a novel method, researchers are able to image and label proteins found in each brain cell from a single tissue sample.
Video: Melanie Gonick/MIT (protein imaging renderings courtesy of Kwanghun Chung and Evan Murray)
Label, rinse, repeat
The key advance of the new technology, known as SWITCH, is the ability to preserve tissue in such a way that it can be imaged repeatedly, with different proteins labeled each time.
To achieve that, the researchers devised a method for controlling the chemical reactions required for tissue preservation and labeling. This allows them to first preserve the tissue, then label a certain protein and image it. They can then wash away the tagging molecule and label a different protein, over and over again.
Controlling the chemical reactions requires a pair of buffers — solutions of weak acids and bases — that alter the tissue’s environment. One of the buffers, known as SWITCH-Off, halts most chemical reactions in the tissue, while the SWITCH-On buffer allows them to resume.
To prepare the tissue samples, the researchers first add the SWITCH-Off buffer, followed by chemicals necessary for tissue preservation, the most important of which is glutaraldehyde. Because the chemicals cannot react with any cells, they diffuse evenly throughout the sample. “It’s like these chemicals are in a stealth mode. They are not detected by tissue,” Chung says.
When the researchers add the SWITCH-On buffer, the glutaraldehyde forms a gel that preserves the tissue. The researchers also add detergent to destroy the lipids of the cell membranes, making the cell interiors more visible to a light microscope.
Once the tissue is preserved and ready for imaging, the researchers add the SWITCH-Off buffer again. With the tissue in an unreactive state, they add labels such as antibodies or dyes, which can be tailored to detect not only proteins but also DNA, neurotransmitters, or lipids. Once the labels have diffused through the tissue, adding the SWITCH-On buffer allows all cells to be exposed to the labels simultaneously.
Protein analysis
In the Cell study, the researchers labeled 22 different proteins in a small section of human brain tissue (roughly 3 millimeters by 3 millimeters by 0.1 millimeters). After 22 rounds of labeling, the tissue was still in good condition, so the researchers believe this technique could be used to image even more proteins.
They also examined the distribution of six proteins in human visual cortex tissue and were able to label and image the myelinated fibers that connect different regions of the brain. “If you can visualize these fibers then you can really understand brain connectivity and the fundamental laws that govern how these wires are formed and connected,” Chung says.
The size of the tissue that can be imaged is limited only by the amount of time required for labeling the proteins and imaging the sample.
It takes about a month for each labeling molecule to diffuse through a cubic-centimeter-sized tissue sample, but Chung and colleagues recently reported in the Proceedings of the National Academy of Sciences that they could speed this up dramatically by exposing the tissue to a randomly changing electric field. This cuts the diffusion time to about a day.
The imaging time depends on the type of microscope used. For this study, the researchers used a light sheet microscope, which can image samples about 100 times faster than a traditional light microscope. Using this microscope, it took about two hours to image an entire mouse brain, compared to about three days with a traditional microscope.
“There are other ways of doing proteomic imaging, but many of them are two-dimensional, or not scalable, or require special equipment,” Chung says. “But with this technique, anyone can do it and it’s scalable.”
Robert Brown, chair of neurology at the University of Massachusetts Medical School, says the new technique is part of a “new generation of imaging technology based on careful manipulation of biochemical structures.”
“It’s extraordinary because it allows one to look for multiple targets simultaneously in the same cell, with three-dimensional resolution, which has not been feasible with previous imaging methods,” he adds.
Chung’s lab will make detailed protocols and other resources available through its website. He now plans to start using SWITCH to study human neurological disorders and is also working on other technologies to help map the human brain.
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Singing in the brain
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Male zebra finches, small songbirds native to central Australia, learn their songs by copying what they hear from their fathers. These songs, often used as mating calls, develop early in life as juvenile birds experiment with mimicking the sounds they hear.
MIT neuroscientists have now uncovered the brain activity that supports this learning process. Sequences of neural activity that encode the birds’ first song syllable are duplicated and altered slightly, allowing the birds to produce several variations on the original syllable. Eventually these syllables are strung together into the bird’s signature song, which remains constant for life.
“The advantage here is that in order to learn new syllables, you don’t have to learn them from scratch. You can reuse what you’ve learned and modify it slightly. We think it’s an efficient way to learn various types of syllables,” says Tatsuo Okubo, a former MIT graduate student and lead author of the study, which appears in the Nov. 30 online edition of Nature.
Okubo and his colleagues believe that this type of neural sequence duplication may also underlie other types of motor learning. For example, the sequence used to swing a tennis racket might be repurposed for a similar motion such as playing Ping-Pong. “This seems like a way that sequences might be learned and reused for anything that involves timing,” says Emily Mackevicius, an MIT graduate student who is also an author of the paper.
The paper’s senior author is Michale Fee, a professor of brain and cognitive sciences at MIT and a member of the McGovern Institute for Brain Research.
Bursting into song
Previous studies from Fee’s lab have found that a part of the brain’s cortex known as the HVC is critical for song production.
Typically, each song lasts for about one second and consists of multiple syllables. Fee’s lab has found that in adult birds, individual HVC neurons show a very brief burst of activity — about 10 milliseconds or less — at one moment during the song. Different sets of neurons are active at different times, and collectively the song is represented by this sequence of bursts.
In the new Nature study, the researchers wanted to figure out how those neural patterns develop in newly hatched zebra finches. To do that, they recorded electrical activity in HVC neurons for up to three months after the birds hatched.
When zebra finches begin to sing, about 30 days after hatching, they produce only nonsense syllables known as subsong, similar to the babble of human babies. At first, the duration of these syllables is highly variable, but after a week or so they turn into more consistent sounds called protosyllables, which last about 100 milliseconds. Each bird learns one protosyllable that forms a scaffold for subsequent syllables.
The researchers found that within the HVC, neurons fire in a sequence of short bursts corresponding to the first protosyllable that each bird learns. Most of the neurons in the HVC participate in this original sequence, but as time goes by, some of these neurons are extracted from the original sequence and produce a new, very similar sequence. This chain of neural sequences can be repurposed to produce different syllables.
“From that short sequence it splits into new sequences for the next new syllables,” Mackevicius says. “It starts with that short chain that has a lot of redundancy in it, and splits off some neurons for syllable A and some neurons for syllable B.”
This splitting of neural sequences happens repeatedly until the birds can produce between three and seven different syllables, the researchers found. This entire process takes about two months, at which point each bird has settled on its final song.
“This is a very natural way for motor patterns to evolve, by repeating something and then molding it, but until now nobody had any good data to understand how the brain actually does that,” says Ofer Tchernichovski, a professor of psychology at Hunter College who was not involved in the research. “What’s cool about this paper is they managed to follow how brain centers govern these transitions from simple repetitive patterns to more complex patterns."
Evolution by duplication
The researchers note that this process is similar to what is believed to drive the production of new genes and traits during evolution.
“If you duplicate a gene, then you could have separate mutations in both copies of the gene and they could eventually do different functions,” Okubo says. “It’s similar with motor programs. You can duplicate the sequence and then independently modify the two daughter motor programs so that they can now each do slightly different things.”
Mackevicius is now studying how input from sound-processing parts of the brain to the HVC contributes to the formation of these neural sequences.
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How neurons lose their connections
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Strengthening and weakening the connections between neurons, known as synapses, is vital to the brain’s development and everyday function. One way that neurons weaken their synapses is by swallowing up receptors on their surfaces that normally respond to glutamate, one of the brain’s excitatory chemicals.
In a new study, MIT neuroscientists have detailed how this receptor reabsorption takes place, allowing neurons to get rid of unwanted connections and to dampen their sensitivity in cases of overexcitation.
“Pulling in and putting out receptors is a dynamic process, and it’s highly regulated by a neuron’s environment,” says Elly Nedivi, a professor of brain and cognitive sciences and member of MIT’s Picower Institute for Learning and Memory. “Our understanding of how receptors are pulled in and how regulatory pathways impact that has been quite poor.”
Nedivi and colleagues found that a protein known as CPG2 is key to this regulation, which is notable because mutations in the human version of CPG2 have been previously linked to bipolar disorder. “This sets the stage for testing various human mutations and their impact at the cellular level,” says Nedivi, who is the senior author of a Jan. 14 Current Biology paper describing the findings.
The paper’s lead author is former Picower Institute postdoc Sven Loebrich. Other authors are technical assistant Marc Benoit, recent MIT graduate Jaclyn Konopka, former postdoc Joanne Gibson, and Jeffrey Cottrell, the director of translational research at the Stanley Center for Psychiatric Research at the Broad Institute.
Forming a bridge
Neurons communicate at synapses via neurotransmitters such as glutamate, which flow from the presynaptic to the postsynaptic neuron. This communication allows the brain to coordinate activity and store information such as new memories.
Previous studies have shown that postsynaptic cells can actively pull in some of their receptors in a phenomenon known as long-term depression (LTD). This important process allows cells to weaken and eventually eliminate poor connections, as well as to recalibrate their set point for further excitation. It can also protect them from overexcitation by making them less sensitive to an ongoing stimulus.
Pulling in receptors requires the cytoskeleton, which provides the physical power, and a specialized complex of proteins known as the endocytic machinery. This machinery performs endocytosis — the process of pulling in a section of the cell membrane in the form of a vesicle, along with anything attached to its surface. At the synapse, this process is used to internalize receptors.
Until now, it was unknown how the cytoskeleton and the endocytic machinery were linked. In the new study, Nedivi’s team found that the CPG2 protein forms a bridge between the cytoskeleton and the endocytic machinery.
“CPG2 acts like a tether for the endocytic machinery, which the cytoskeleton can use to pull in the vesicles,” Nedivi says. “The glutamate receptors that are in the membrane will get pinched off and internalized.”
They also found that CPG2 binds to the endocytic machinery through a protein called EndoB2. This CPG2-EndoB2 interaction occurs only during receptor internalization provoked by synaptic stimulation and is distinct from the constant recycling of glutamate receptors that also occurs in cells. Nedivi’s lab has previously shown that this process, which does not change the cells’ overall sensitivity to glutamate, is also governed by CPG2.
“This study is intriguing because it shows that by engaging different complexes, CPG2 can regulate different types of endocytosis,” says Linda Van Aelst, a professor at Cold Spring Harbor Laboratory who was not involved in the research.
When synapses are too active, it appears that an enzyme called protein kinase A (PKA) binds to CPG2 and causes it to launch activity-dependent receptor absorption. CPG2 may also be controlled by other factors that regulate PKA, including hormone levels, Nedivi says.
Link to bipolar disorder
In 2011, a large consortium including researchers from the Broad Institute discovered that a gene called SYNE1 is number two on the hit list of genes linked to susceptibility for bipolar disorder. They were excited to find that this gene encoded CPG2, a regulator of glutamate receptors, given prior evidence implicating these receptors in bipolar disorder.
In a study published in December, Nedivi and colleagues, including Loebrich and co-lead author Mette Rathje, identified and isolated the human messenger RNA that encodes CPG2. They showed that when rat CPG2 was knocked out, its function could be restored by the human version of the protein, suggesting both versions have the same cellular function.
Rathje, a Picower Institute postdoc in Nedivi’s lab, is now studying mutations in human CPG2 that have been linked to bipolar disorder. She is testing their effect on synaptic function in rats, in hopes of revealing how those mutations might disrupt synapses and influence the development of the disorder.
Nedivi suspects that CPG2 is one player in a constellation of genes that influence susceptibility to bipolar disorder.
“My prediction would be that in the general population there’s a range of CPG2 function, in terms of efficacy,” Nedivi says. “Within that range, it will depend what the rest of the genetic and environmental constellation is, to determine whether it gets to the point of causing a disease state.”
The research was funded by the Picower Institute Innovation Fund and the Gail Steel Fund for Bipolar Research.
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