Posts tagged NMDA receptor
Articles and news from the latest research reports.
Compound from hops aids cognitive function in young animals
Xanthohumol, a type of flavonoid found in hops and beer, has been shown in a new study to improve cognitive function in young mice, but not in older animals.
The research was just published in Behavioral Brain Research by scientists from the Linus Pauling Institute and College of Veterinary Medicine at Oregon State University. It’s another step toward understanding, and ultimately reducing the degradation of memory that happens with age in many mammalian species, including humans.
Flavonoids are compounds found in plants that often give them their color. The study of them – whether in blueberries, dark chocolate or red wine - has increased in recent years due to their apparent nutritional benefits, on issues ranging from cancer to inflammation or cardiovascular disease. Several have also been shown to be important in cognition.
Xanthohumol has been of particular interest because of possible value in treating metabolic syndrome, a condition associated with obesity, high blood pressure and other concerns, including age-related deficits in memory. The compound has been used successfully to lower body weight and blood sugar in a rat model of obesity.
The new research studied use of xanthohumol in high dosages, far beyond what could be obtained just by diet. At least in young animals, it appeared to enhance their ability to adapt to changes in the environment. This cognitive flexibility was tested with a special type of maze designed for that purpose.
“Our goal was to determine whether xanthohumol could affect a process we call palmitoylation, which is a normal biological process but in older animals may become harmful,” said Daniel Zamzow, a former OSU doctoral student and now a lecturer at the University of Wisconsin/Rock County.
“Xanthohumol can speed the metabolism, reduce fatty acids in the liver and, at least with young mice, appeared to improve their cognitive flexibility, or higher level thinking,” Zamzow said. “Unfortunately it did not reduce palmitoylation in older mice, or improve their learning or cognitive performance, at least in the amounts of the compound we gave them.”
Kathy Magnusson, a professor in the OSU Department of Biomedical Sciences, principal investigator with the Linus Pauling Institute and corresponding author on this study, said that xanthohumol continues to be of significant interest for its biological properties, as are many other flavonoids.
“This flavonoid and others may have a function in the optimal ability to form memories,” Magnusson said. “Part of what this study seems to be suggesting is that it’s important to begin early in life to gain the full benefits of healthy nutrition.”
It’s also important to note, Magnusson said, that the levels of xanthohumol used in this study were only possible with supplements. As a fairly rare micronutrient, the only normal dietary source of it would be through the hops used in making beer, and “a human would have to drink 2000 liters of beer a day to reach the xanthohumol levels we used in this research.”
In this and other research, Magnusson’s research has primarily focused on two subunits of the NMDA receptor, called GluN1 and GluN2B. Their decline with age appears to be related to the decreased ability to form and quickly recall memories.
In humans, many adults start to experience deficits in memory around the age of 50, and some aspects of cognition begin to decline around age 40, the researchers noted in their report.
(Source: oregonstate.edu)
Research gives unprecedented 3-D view of important brain receptor
Researchers with Oregon Health & Science University’s Vollum Institute have given science a new and unprecedented 3-D view of one of the most important receptors in the brain — a receptor that allows us to learn and remember, and whose dysfunction is involved in a wide range of neurological diseases and conditions, including Alzheimer’s, Parkinson’s, schizophrenia and depression.
The unprecedented view provided by the OHSU research, published online June 22 in the journal Nature, gives scientists new insight into how the receptor — called the NMDA receptor — is structured. And importantly, the new detailed view gives vital clues to developing drugs to combat the neurological diseases and conditions.
"This is the most exciting moment of my career," said Eric Gouaux, a senior scientist at the Vollum Institute and a Howard Hughes Medical Institute investigator. "The NMDA receptor is one of the most essential, and still sometimes mysterious, receptors in our brain. Now, with this work, we can see it in fascinating detail."
Receptors facilitate chemical and electrical signals between neurons in the brain, allowing those neurons to communicate with each other. The NMDA (N-methyl-D-aspartate) receptor is one of the most important brain receptors, as it facilitates neuron communication that is the foundation of memory, learning and thought. Malfunction of the NMDA receptor occurs when it is increasingly or decreasingly active and is associated with a wide range of neurological disorders and diseases. Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia and epilepsy are, in many instances, linked to problems with NMDA activity.
Scientists across the world study the NMDA receptor; some of the most notable discoveries about the receptor during the past three decades have been made by OHSU Vollum scientists.
The NMDA receptor makeup includes receptor “subunits” — all of which have distinct properties and act in distinct ways in the brain, sometimes causing neurological problems. Prior to Gouaux’s study, scientists had only a limited view of how those subtypes were arranged in the NMDA receptor complex and how they interacted to carry out specific functions within the brain and central nervous system.
Gouaux’s team of scientists – Chia-Hsueh Lee, Wei Lu, Jennifer Michel, April Goehring, Juan Du and Xianqiang Song – created a 3-D model of the NMDA receptor through a process called X-ray crystallography. This process throws x-ray beams at crystals of the receptor; a computer calibrates the makeup of the structure based on how those x-ray beams bounce off the crystals. The resulting 3-D model of the receptor, which looks something like a bouquet of flowers, shows where the receptor subunits are located, and gives unprecedented insight into their actions.
"This new detailed view will be invaluable as we try to develop drugs that might work on specific subunits and therefore help fight or cure some of these neurological diseases and conditions," Gouaux said. "Seeing the structure in more detail can unlock some of its secrets — and may help a lot of people."
Unprecedented detail of intact neuronal receptor offers blueprint for drug developers
Biologists at Cold Spring Harbor Laboratory (CSHL) report today that they have succeeded in obtaining an unprecedented view of a type of brain-cell receptor that is implicated in a range of neurological illnesses, including Alzheimer’s disease, Parkinson’s disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.
The team’s atomic-level picture of the intact NMDA (N-methyl, D-aspartate) receptor should serve as template and guide for the design of therapeutic compounds.
The NMDA receptor is a massive multi-subunit complex that integrates both chemical and electrical signals in the brain to allow neurons to communicate with one another. These conversations form the basis of memory, learning, and thought, and critically mediate brain development. The receptor’s function is tightly regulated: both increased and decreased NMDA activities are associated with neurological diseases.
Despite the importance of NMDA receptor function, scientists have struggled to understand how it is controlled. In work published today in Science, CSHL Associate Professor Hiro Furukawa and Erkan Karakas, Ph.D., a postdoctoral investigator, use a type of molecular photography known as X-ray crystallography to determine the structure of the intact receptor. Their work identifies numerous interactions between the four subunits of the receptor and offers new insight into how the complex is regulated.
“Previously, our group and others have crystallized individual subunits of the receptor – just fragments – but that simply was not enough,” says Furukawa. “To understand how this complex functions you need to see it all together, fully assembled.”
For such a large complex, this was a challenging task. Using an exhaustive array of protein purification methods, Furukawa and Karakas were able to isolate the intact receptor. Their crystal structure reveals that the receptor looks much like a hot air balloon. “The ‘basket’ is what we call the transmembrane domain. It forms an ion channel that allows electrical signals to propagate through the neuron,” explains Furukawa.
An ion channel is like a gate in the neuronal membrane. Ions, small electrically charged atoms, are unable to pass through the cell membrane. When the ion channel “gate” is closed, ions congregate outside the cell, creating an electrical potential across the cell membrane.
When the ion channel “gate” opens, ions flow in and out of the cell through the channel pores. This generates an electrical current that sums up to create pulses that rapidly propagate through the neuron. But the current can’t jump from one neuron to the next. Rather, the electrical pulse triggers the release of chemical messengers, called neurotransmitters. These molecules traverse the distance between the neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells. There, they act much like a key, unlocking ion channels within the receptor and propelling the electrical signal across another neuron and, ultimately, across the brain.
The “balloon” portion of the receptor that Furukawa describes is found outside the cell. This is the region that binds to neurotransmitters. The structure of the assembled multi-subunit receptor complex, including the elusive ion channel, helps to explain some of the existing data about how NMDA receptors function. “We are able to see how one domain on the exterior side of the receptor directly regulates the ion channel within the membrane,” says Furukawa. “Our structure shows why this particular domain, called the amino terminal domain, is important for the activity of the NMDA receptor, but not for other related receptors.”
This information will be critical as scientists work to develop drugs that control the NMDA receptor. “Our structure defines the interfaces where multiple subunits and domains contact one another,” says Furukawa. “In the future, these will guide the design of therapeutic compounds to treat a wide range of devastating neurological diseases.”
Turning off major memory switch dulls memories
A faultily formed memory sounds like hitting random notes on a keyboard while a proper one sounds more like a song, scientists say.
When they turned off a major switch for learning and memory, brain cells communicated, but the relationship was superficial, said Dr. Joe Tsien, neuroscientist at the Medical College of Georgia at Georgia Regents University and Co-Director of the GRU Brain & Behavior Discovery Institute.
“We have begun to crack the neural code, which allows us to look in real time at how thoughts happen and how memories are made,” Tsien said. “That has enabled us to understand for the first time how and whether the right keys are struck at the right time and in the right place and manner to make the beautiful sound of coherent memories and to compare what happens when a key element is missing.”
With the NMDA receptor intact, chatter reverberates, associations are made and helpful memories – like how touching a hot stove results in a burn – are easily retrieved.
“You see a face and think of a name, you see your office, and you think you need to work; everything is associative,” said Tsien, corresponding author of the study in the journal PLOS ONE. “But in mice lacking an NMDA receptor, you can tell the memory patterns are dull and dissociated.”
Using the century-old Pavlovian conditioning model that first showed how repetition creates association, they found that mice lacking a functioning NMDA receptor in the hippocampus, the brain’s center of learning and memory, could not recollect even something fearful.
When they played a tone, followed 20 seconds later by a mild foot shock, normal mice quickly made the association, down to the timing. The connection essentially never registered with mice lacking the NMDA receptor. Healthy brain recalling memories and Amnesic brain recalling contextual memories
“They form the initial patterns, but don’t rehearse them,” said Tsien. “Their tones are flat, the association is poor, while everything we register in the healthy brain is associative.” To illustrate just how flat, Postdoctoral Fellow Hui Kuang assigned musical notes to the memory activity of each, which resulted in random noise by the NMDA knockout mice compared to a dynamic rhythm from normal mice.
“By knowing what these patterns look like and what they mean, you can use this signature to measure, for example, during aging, why we begin to lose memory and to identify and test drugs that are truly effective at aiding memory,” Tsien said.
“You can tell whether there is an issue with reverberation, whether your brain is repeating what you need to remember, or repeats it but somehow stores it badly, so it’s not associated with the right things. This study has revealed a lot of fascinating details about what neuroscientists call the brain’s neural code” Tsien said.”
He wants to look at how aging affects these processes as a next step. The research team also is looking at Doogie, a mouse genetically bred by Tsien and his team in 1999 to be exceptionally smart, to see if they can also learn more about how super memories are made and what they look like.
This ability to decode how and what the brain is remembering, should one day help physicians better assess and treat conditions such as Alzheimer’s and schizophrenia, Tsien said. They may find that some answers are already out there, such as drugs that boost reverberation, or a stimulant like caffeine to help retrieve a memory, Tsien said.
His team first reported decoding brain cell conversations as memories were formed and recalled in PLOS ONE in 2009. As with the new study, they used a computational algorithm to translate the neuronal conversations into some of the first pictures of what memories look like.