Posts tagged NMDA receptors
Articles and news from the latest research reports.
Xenon Exposure Shown to Erase Traumatic Memories
McLean Hospital researchers are reporting that xenon gas, used in humans for anesthesia and diagnostic imaging, has the potential to be a treatment for post-traumatic stress disorder (PTSD) and other memory-related disorders.
“In our study, we found that xenon gas has the capability of reducing memories of traumatic events,” said Edward G. Meloni, PhD, assistant psychologist at McLean Hospital and an assistant professor of Psychiatry at Harvard Medical School. “It’s an exciting breakthrough, as this has the potential to be a new treatment for individuals suffering from PTSD.”
In the study, published in the current issue of PLOS ONE, Meloni, and Marc J. Kaufman, PhD, director of the McLean Hospital Translational Imaging Laboratory, examined whether a low concentration of xenon gas could interfere with a process called reconsolidation – a state in which reactivated memories become susceptible to modification. “We know from previous research that each time an emotional memory is recalled, the brain actually restores it as if it were a new memory. With this knowledge, we decided to see whether we could alter the process by introducing xenon gas immediately after a fear memory was reactivated,” explained Meloni.
The investigators used an animal model of PTSD called fear-conditioning to train rats to be afraid of environmental cues that were paired with brief footshocks. Reactivating the fearful memory was done by exposing the rats to those same cues and measuring their freezing response as a readout of fear. “We found that a single exposure to the gas, which is known to block NMDA receptors involved in memory formation in the brain, dramatically and persistently reduced fear responses for up to 2 weeks. It was as though the animals no longer remembered to be afraid of those cues”, said Dr. Meloni.
Meloni points out that the inherent properties of a gas such as xenon make it especially attractive for targeting dynamic processes such as memory reconsolidation. “Unlike other drugs or medications that may also block NMDA receptors involved in memory, xenon gets in and out of the brain very quickly. This suggests that xenon could be given at the exact time the memory is reactivated, and for a limited amount of time, which may be key features for any potential therapy used in humans.”
“The fact that we were able to inhibit remembering of a traumatic memory with xenon is very promising because it is currently used in humans for other purposes, and thus it could be repurposed to treat PTSD,” added Kaufman.
For these investigators, several questions remain to be addressed with further testing. “From here we want to explore whether lower xenon doses or shorter exposure times would also block memory reconsolidation and the expression of fear. We’d also like to know if xenon is as effective at reducing traumatic memories from past events, so-called remote memories, versus the newly formed ones we tested in our study”.
Meloni and Kaufman indicate that future studies are planned to test if the effects of xenon in rats seen in their study translate to humans. Given that intrusive re-experiencing of traumatic memories – including flashbacks, nightmares, and distress and physiological reactions induced when confronted with trauma reminders – is a hallmark symptom for many who suffer from PTSD, a treatment that alleviates the impact of those painful memories could provide welcome relief.
(Source: mcleanhospital.org)
The role of lactate in boosting memory
Everyone knows that neurons are the key to how the brain operates. But it turns out they aren’t the only stars in the show; neighboring cells called astrocytes are quickly gaining increasing respect for the critical role they play in memory and learning. EPFL scientists have recently outlined the molecular mechanics of this process in an article published in Proceedings of the National Academy of Sciences (PNAS). Lactate produced by the star-shaped astrocytes accelerates the memorization process. This result, surprising until very recently, opens up new possibilities for treating cognitive and memory disorders, as well as psychiatric conditions such as depression.
Our brains are greedy, gobbling up as much as 25% of our daily energy consumption. Neurons and astrocytes thrive on glucose. Neurons use it to protect themselves from the buildup of toxic products resulting from their activity. Astrocytes, which are glial cells (as opposed to neurons), manufacture lactate; this was long thought to be a byproduct of glucose metabolism, and then as a simple energy source for neurons.
In 2011, research published in the journal Cell by EPFL’s Laboratory of Neuroenergetics and Cellular Dynamics in collaboration with a U.S. team unveiled the critical role of lactate. “In vivo, when the transfer of lactate from astrocytes to neurons is blocked, we found that the memorization process was also blocked,” explains EPFL professor Pierre Magistretti, head of the lab. “We thus knew that it was an essential fuel for that process.”
Focusing their attention on the molecular mechanism, the scientists discovered that lactate provides more than just energy. It acts as a moderator of one type of glutamate receptor (NMDA receptors), the nervous system’s primary neurotransmitter. This glutamate receptor is involved in the memorization process, and the research demonstrates that lactate gives them what amounts to a turbo-boost. “Glutamate lets you drive in first gear; with lactate, you can shift into fourth and travel at 100 km/h,” says Magistretti.
Palliating cognitive deficits
The scientists did their initial research in vitro. They exposed mice neurons to various substances and measured their effect on the expression of genes involved in memory. Glucose and pyruvate (another glucose derivative) didn’t have any effect. A lactate supplement, on the other hand, triggered the expression of four genes involved in cerebral plasticity that are essential to memorization.
They followed this work with in vivo studies, which confirmed their results. They administered lactate into the brains of living mice, and then extracted the tissues and measured gene expression. Once again, the expression of genes involved in cerebral plasticity increased significantly.
Could we take lactate supplements and develop encyclopedic memory? Magistretti’s lab has just received a grant to study the effects of artificial lactate supplementation. “We have identified a series of molecules that can make astrocytes produce more lactate. Now the idea is to see in vivo if we can mitigate cognitive deficits and memory disorders.” In addition, since conditions such as depression are often accompanied by cognitive problems, “lactate could also have an antidepressant effect,” says Magistretti, who also conducts research at the National Center for Competence in Research Synapsy, dedicated to the understanding of the synaptic basis of psychiatric disease.
(Source: actu.epfl.ch)
Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
NMDA receptor (NMDAR)-induced excitotoxicity is thought to contribute to the cell death associated with certain neurodegenerative diseases, stroke, epilepsy, and traumatic brain injury. Targeting NMDARs therapeutically is complicated by the fact that cell signaling downstream of their activation can promote cell survival and plasticity as well as excitotoxicity. However, research over the past decade has suggested that overactivation of NMDARs located outside of the synapse plays a major role in NMDAR toxicity, whereas physiological activation of those inside the synapse can contribute to cell survival, raising the possibility of therapeutic intervention based on NMDAR subcellular localization. Here, we review the evidence both supporting and refuting this localization hypothesis of NMDAR function and discuss the role of NMDAR localization in disorders of the nervous system. Preventing excessive extrasynaptic NMDAR activation may provide therapeutic benefit, particularly in Alzheimer disease and Huntington disease.
Unprecedented structural insights reveal how NMDA receptors can be blocked, to limit neurotoxicity
Structural biologists at Cold Spring Harbor Laboratory (CSHL) and collaborators at Emory University have obtained important scientific results likely to advance efforts to develop new drugs targeting NMDA receptors in the brain.
NMDA (N-methyl D-aspartate) receptors are found on the surface of many nerve cells and are involved in signaling that is essential in basic brain functions including learning and memory formation. Problems with their function have been implicated in depression, schizophrenia, Alzheimer’s and Parkinson’s diseases, as well as brain damage caused by stroke.
Normally, NMDA receptors are activated by glutamate, the most common neurotransmitter of excitatory cell-to-cell messages in the brain.
Overactivation of NMDA receptors is a known cause of nerve-cell toxicity. Thus, drug developers have long sought compounds that can selectively block or antagonize NMDA receptors, while not affecting other types of glutamate receptors in the brain, whose function is essential.
However, a basic question — how those compounds bind and antagonize NMDA receptors — has not been understood at the molecular level.
Over a period of years, CSHL Associate Professor Hiro Furukawa and colleagues have taken a step-by-step approach to learn about the precise shape of various subunits of the complex NMDA receptor protein, and demonstrating the relationship between different versions of the receptor’s shape and its function. (see more here) Since the subunits have different biological roles, they have to be specifically targeted by drug compounds to obtain specific effects.
Furukawa’s team has used a technique called x-ray crystallography to map various domains of the protein while it is bound to different chemical compounds, or antagonists, that downregulate its function. Today in the journal Neuron they publish the first crystal structures of two NMDA receptor subunits (called GluN1 and GluN2A) in complex with four different compounds known to have the capacity to inhibit, or antagonize, NMDA receptor function.
Showing this two-unit ligand binding domain (LBD) in complex with NMDA antagonists — potential drugs — reveals that each antagonist has a distinctive mode of binding the LBD. In essence, the “docking port” is held open, but to a different extent when different antagonists are bound. The study also reveals an element in the antagonist binding site that is only present in GluN2A subunit, but not in the others. This previously hidden information, says Furukawa, is critical: “It indicates different strategies to develop therapeutic compounds – ones that bind to a certain type of NMDA receptors very specifically. Being able to target specific subtypes of the receptor is of enormous interest and has great therapeutic potential in a range of illnesses and injuries affecting the brain.”
Long-term memory in the cortex
Game changing results: Brain uses the cortex for making sensory associations, not the hippocampus
‘Where’ and ‘how’ memories are encoded in a nervous system is one of the most challenging questions in biological research. The formation and recall of associative memories is essential for an independent life. The hippocampus has long been considered a centre in the brain for the long-term storage of spatial associations. Now, Mazahir T. Hasan at the Max Planck Institute for Medical Research and José Maria Delgado-Garcìa at the University Pablo de Olavide of Seville, Spain, were able to provide first experimental evidence that a specific form of memory associations is encoded in the cerebral cortex and is not localized in the hippocampus as described in most Neuroscience textbooks. The new study is a game changer since it strongly suggests that the motor cortical circuits itself, and not the hippocampus, is used as memory storage.
Henry Molaison, known widely as H.M., is a famous name in memory research. Large parts of the American‘s hippocampus – the region of the brain that is a major element in learning and memory processes – were removed in the 1950s in an attempt to cure his epileptic seizures. He subsequently suffered severe memory lapses and was no longer able to remember virtually anything new he had learned. Most scientists thereby concluded that the hippocampus is the site of long-term memory.
However, the extent of H.M.’s brain damage was obviously underestimated, because other regions in addition to the hippocampus were also removed or damaged in the surgical procedure. The researchers from Heidelberg and Seville have therefore investigated the learning behaviour of genetically modified mice in which NMDA receptors are turned off only in the motor cerebral cortex. NMDA receptors bind the neurotransmitter glutamate to the synapses and become active when several signals feed into one synapse at the same time. They are the central molecular elements of learning processes, being involved in increasing or decreasing transmission of the signals to synapses.
As the new study shows, in the motor cortex this so-called synaptic plasticity no longer functions without the NMDA receptors. The scientists were thus able to rule out the hippocampus or other regions as the cause for their observations. Based on the new findings, it is the cerebral cortex, not the hippocampus that is the storage site for some forms of memory.
In behaviour tests, so called eyeblink conditioning, animals with and without NMDA receptors in the primary motor cortex had to learn to link a tone with a subsequent electrical stimulus of the eyelid. This association of two sensory inputs involves the cerebellum which coordinates the necessary movements, as well as the hippocampus and the cerebral cortex, which are important learning and memory centres. “After a learning phase, the animals’ reflex is to close their eye when they hear just the tone. Without NMDA receptors in the primary motor cerebral cortex, the genetically modified mice on the other hand cannot remember the connection between the tone and electrical stimulus, and therefore they keep their eyes open despite the tone”, explains Mazahir T. Hasan of the Max Planck Institute for Medical Research.
The researchers have thus complemented the findings of their Heidelberg-based colleagues that the hippocampus is not the seat of memory. In July 2012, Rolf Sprengel and Peter Seeburg from the Max Planck Institute for Medical Research discovered that mice without NMDA receptors in the hippocampus are still quite capable of learning. “We now think that the hippocampus provides the necessary environmental cues, which are transmitted to the cortex where learning-dependent associations take place. Memories are thus stored at various sites in the cerebral cortex on a long-term basis”, explains Hasan.
The findings of Hasan and Delgado-Garcìa thus represent a paradigm-shift in memory research as they make clear that the cerebral cortex is the brain region where memory associations are linked and stored – not the hippocampus. An advanced and detailed knowledge of the mechanisms for the acquisition, consolidation, and recall of associations in the brain is the prerequisite for a therapeutic treatment of the devastating effects of memory loss in various neurological diseases, such as amnesia, Alzheimer`s disease and dementia.
Newly Discovered ‘Switch’ Plays Dual Role In Memory Formation
Researchers at Johns Hopkins have uncovered a protein switch that can either increase or decrease memory-building activity in brain cells, depending on the signals it detects. Its dual role means the protein is key to understanding the complex network of signals that shapes our brain’s circuitry, the researchers say. A description of their discovery appears in the July 31 issue of the Journal of Neuroscience.
“What’s interesting about this protein, AGAP3, is that it is effectively double-sided: One side beefs up synapses in response to brain activity, while the other side helps bring synapse-building back down to the brain’s resting state,” says Richard Huganir, Ph.D., a professor and director of the Solomon H. Snyder Department of Neuroscience at the Johns Hopkins University School of Medicine and co-director of the Brain Science Institute at Johns Hopkins. “The fact that it links these two opposing activities indicates AGAP3 may turn out to be central to controlling the strength of synapses.”
Huganir has long studied how connections between brain cells, known as synapses, are strengthened and weakened to form or erase memories. The new discovery came about when he and postdoctoral fellow Yuko Oku, Ph.D., investigated the chain reaction of signals involved in one type of synaptic strengthening.
In a study of the proteins that interact with one of the known proteins from that chain reaction, the previously unknown AGAP3 turned up. It contained not only a site designed to bind another protein involved in the chain reaction that leads from brain stimulation to learning, but also a second site involved in bringing synapse-building activity down to normal levels after a burst of activity.
Although it might seem the two different functions are behaving at cross-purposes, Oku says, it also could be that nature’s bundling of these functions together in a single protein is an elegant way of enabling learning and memory while preventing dangerous overstimulation. More research is needed, Oku says, to figure out whether AGAP3’s two sites coordinate by affecting each other’s activity, or are effectively free agents.
Cognitive decline with age is normal, routine – but not inevitable
If you forget where you put your car keys and you can’t seem to remember things as well as you used to, the problem may well be with the GluN2B subunits in your NMDA receptors.
And don’t be surprised if by tomorrow you can’t remember the name of those darned subunits.
They help you remember things, but you’ve been losing them almost since the day you were born, and it’s only going to get worse. An old adult may have only half as many of them as a younger person.
Research on these biochemical processes in the Linus Pauling Institute at Oregon State University is making it clear that cognitive decline with age is a natural part of life, and scientists are tracking the problem down to highly specific components of the brain. Separate from some more serious problems like dementia and Alzheimer’s disease, virtually everyone loses memory-making and cognitive abilities as they age. The process is well under way by the age of 40 and picks up speed after that.
But of considerable interest: It may not have to be that way.
“These are biological processes, and once we fully understand what is going on, we may be able to slow or prevent it,” said Kathy Magnusson, a neuroscientist in the OSU Department of Biomedical Sciences, College of Veterinary Medicine, and professor in the Linus Pauling Institute. “There may be ways to influence it with diet, health habits, continued mental activity or even drugs.”
The processes are complex. In a study just published in the Journal of Neuroscience, researchers found that one protein that stabilizes receptors in a young animal – a good thing conducive to learning and memory – can have just the opposite effect if there’s too much of it in an older animal.
But complexity aside, progress is being made. In recent research, supported by the National Institutes of Health, OSU scientists used a genetic therapy in laboratory mice, in which a virus helped carry complementary DNA into appropriate cells and restored some GluN2B subunits. Tests showed that it helped mice improve their memory and cognitive ability.
The NMDA receptor has been known of for decades, Magnusson said. It plays a role in memory and learning but isn’t active all the time – it takes a fairly strong stimulus of some type to turn it on and allow you to remember something. The routine of getting dressed in the morning is ignored and quickly lost to the fog of time, but the day you had an auto accident earns a permanent etching in your memory.
Within the NMDA receptor are various subunits, and Magnusson said that research keeps pointing back to the GluN2B subunit as one of the most important. Infants and children have lots of them, and as a result are like a sponge in soaking up memories and learning new things. But they gradually dwindle in number with age, and it also appears the ones that are left work less efficiently.
“You can still learn new things and make new memories when you are older, but it’s not as easy,” Magnusson said. “Fewer messages get through, fewer connections get made, and your brain has to work harder.”
Until more specific help is available, she said, some of the best advice for maintaining cognitive function is to keep using your brain. Break old habits, do things different ways. Get physical exercise, maintain a good diet and ensure social interaction. Such activities help keep these “subunits” active and functioning.
Gene therapy such as that already used in mice would probably be a last choice for humans, rather than a first option, Magnusson said. Dietary or drug options would be explored first.
“The one thing that does seem fairly clear is that cognitive decline is not inevitable,” she said. “It’s biological, we’re finding out why it happens, and it appears there are ways we might be able to slow or stop it, perhaps repair the NMDA receptors. If we can determine how to do that without harm, we will.”
(Source: oregonstate.edu)
Study identifies brain circuits involved in learning and decision making
Finding has implications for alcoholism and other patterns of addictive behavior
Research from the National Institutes of Health has identified neural circuits in mice that are involved in the ability to learn and alter behaviors. The findings help to explain the brain processes that govern choice and the ability to adapt behavior based on the end results.
Researchers think this might provide insight into patterns of compulsive behavior such as alcoholism and other addictions.
“Much remains to be understood about exactly how the brain strikes the balance between learning a behavioral response that is consistently rewarded, versus retaining the flexibility to switch to a new, better response,” said Kenneth R. Warren, Ph.D., acting director of the National Institute on Alcohol Abuse and Alcoholism. “These findings give new insight into the process and how it can go awry.”
The study, published online in Nature Neuroscience, indicates that specific circuits in the forebrain play a critical role in choice and adaptive learning.
Like other addictions, alcoholism is a disease in which voluntary control of behavior progressively diminishes and unwanted actions eventually become compulsive. It is thought that the normal brain processes involved in completing everyday activities become redirected toward finding and abusing alcohol.
The research, conducted by investigators from NIAAA, with support from the National Institute of Mental Health and the University of Cambridge, England, used a variety of approaches to study choice.
Researchers used a simple choice task in which mice viewed images on a computer touchscreen and learned to touch a specific image with their nose to get a food reward. Using various techniques to visualize and record neural activity, researchers found that as the mice learned to consistently make a choice, the brain’s dorsal striatum was activated. The dorsal striatum is thought to play an important role in motivation, decision-making, and reward.
Conversely, when the mice later had to shift to a new choice to receive a reward, the dorsal striatum quieted while regions in the prefrontal cortex, an area involved in decision-making and complex cognitive processes, became active.
Building upon these findings, the authors next deleted or pharmacologically blocked a component of nerve cells which normally binds the neurochemical glutamate (specifically, the GluN2B subunit of the NMDA receptor) within two different areas of the brain, the striatum and the frontal cortex. Previous studies have shown that GluN2B plays a role in memory, spatial reference, and attention. Researchers found that making dorsal striatal GluN2B inactive markedly slowed learning, while shutting down GluN2B in the prefrontal cortex made the mice less able to relearn the touchscreen reward task after the reward image was changed.
“These data add to what we understand about the neural control of behavioral flexibility and striatal learning by identifying GluN2B as a critical molecular substrate to both processes,” said the study’s senior author, Andrew Holmes, Ph.D., Laboratory Chief and Principal Investigator of the NIAAA Laboratory of Behavioral and Genomic Neuroscience.
“This is particularly intriguing for future studies because NMDA receptors are a major target for alcohol and contribute to important features of alcoholism, such as withdrawal. These new findings suggest that GluN2B in corticostriatal circuits may also play a key role in driving the transition from controlled drinking to compulsive abuse that characterizes alcoholism.”
(Source: niaaa.nih.gov)
Neurochemical Traffic Signals May Open New Avenues for the Treatment of Schizophrenia
Researchers at Boston University School of Medicine (BUSM) have uncovered important clues about a biochemical pathway in the brain that may one day expand treatment options for schizophrenia. The study, published online in the journal Molecular Pharmacology, was led by faculty within the department of pharmacology and experimental therapeutics at BUSM.
Patients with schizophrenia suffer from a life-long condition that can produce delusions, disordered thinking, and breaks with reality. A number of treatments are available for schizophrenia, but many patients do not respond to these therapies or experience side effects that limit their use.
This research focused on key components of the brain known as NMDA receptors. These receptors are located on nerve cells in the brain and serve as biochemical gates that allow calcium ions (electrical charges) to enter the cell when a neurotransmitter, such as glutamate, binds to the receptor. Proper activation of these receptors is critical for sensory perception, memory and learning, including the transfer of short-term memory into long-term storage. Patients with schizophrenia have poorly functioning or “hypoactive” NMDA receptors, suggesting the possibility of treatment with drugs that positively affect these receptors. Currently the only way to enhance NMDA receptor function is through the use of agents called agonists that directly bind to the receptor on the outer surface of the cell, opening the gates to calcium ions outside the cell.
In this study, the researchers discovered a novel “non-canonical” pathway in which NMDA receptors residing inside the cell are stimulated by a neuroactive steroid to migrate to the cell surface (a process known as trafficking), thus increasing the number of receptors available for glutamate activation. The researchers treated neural cells from the cerebral cortex with the novel steroid pregnenolone sulfate (PregS) and found that the number of working NMDA receptors on the cell surface increased by 60 to 100 percent within 10 minutes. The exact mechanism by which this occurs is not completely clear, but it appears that PregS increases calcium ions within the cell, which in turn produces a green light signal for more frequent trafficking of NMDA receptors to the cell surface.
Although still in the early stages, further research in this area may be instrumental in the development of treatments not only for schizophrenia, but also for other conditions associated with malfunctioning NMDA receptors, such as age-related decreases in memory and learning ability.
Scientists advance understanding of brain receptor; may help fight neurological disorders
For several years, the pharmaceutical industry has tried to develop drugs that target a specific neurotransmitter receptor in the brain, the NMDA receptor. This receptor is present on almost every neuron in the human brain and is involved in learning and memory. NMDA receptors also have been implicated in several neurological and psychiatric conditions such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and depression.
But drug companies have had little success developing clinically effective drugs that target this receptor.
Now, researchers at Oregon Health & Science University’s Vollum Institute believe they may understand why. And what they’ve discovered may help in the development of new therapies for these conditions.
In a paper published in the current issue of the Journal of Neuroscience, OHSU scientists describe their work on NMDA receptors. There are various types of NMDA receptors, resulting from differences in the protein components that make up the receptor. These differences in the protein components produce receptors with varying properties.
As drug companies have worked to develop compounds that manipulate the activity of these receptors, the focus of much of this drug discovery effort has been on a specific NMDA receptor subtype. In their Journal of Neuroscience paper, the OHSU scientists describe their discovery — that the specific receptor subtype that drug companies have seen as a target is an almost nonexistent contributor of NMDA receptor action.
What does exist, the OHSU scientists found, was a different kind of NMDA receptor subtype — one containing two specific protein components, called GluN2A and GluN2B. NMDA receptors containing these two components were not thought to be very common. The OHSU study found that not only was this NMDA receptor subtype more common than previously believed, it was the most common subtype at synapses. And it was far more common than the receptor subtype that has been the target of drug development efforts.
"What our paper shows is that one reason no drugs have worked well to this point may be because that particular NMDA receptor subtype isn’t there in high quantities. The target they’ve been looking for isn’t the target that’s there," said Ken Tovar, Ph.D., a senior postdoctoral fellow at the Vollum Institute. Tovar’s co-authors on the paper were Gary Westbrook, M.D., senior scientist and co-director of the Vollum Institute, and Matthew McGinley, Ph.D., a former graduate student in the Westbrook laboratory.
Tovar said these findings could provide a new target for drug development.
"If you know what’s there, then you know what to go after — you just have to figure out how to do it," Tovar said.
The OHSU study also provides clues into how the function of this most common NMDA receptor subtype might be manipulated. Highly specific drugs interact with either GluN2A or GluN2B. Tovar and colleagues demonstrated that when GluN2A and GluN2B coexist in the same receptor, molecules that targeted GluN2A change the behavior of the receptor in ways that could be clinically beneficial.
"NMDA receptors have been implicated in a diverse list of neurological and psychiatric conditions. Thus, the more we know about how to modulate the behavior of the receptors that are there — at synapses — the greater chance we have of finding drugs to treat these conditions," Tovar said.
"From the perspective of drug development, knowing the nature of your target is one way to keep drug development costs down," said Tovar. "Spending resources investigating a target that turns out to be unimportant means those costs get passed on to the drugs that are effective."
(Image: iStockphoto)