Posts tagged AMPA receptors
Articles and news from the latest research reports.
(Image caption: The structure determines the function: AMPA receptors in the nerve cells of the brain are composed of a range of more than 30 different proteins. Source: Bernd Fakler)
Understanding the Components of Memory
Dr. Uwe Schulte, Dr. Jochen Schwenk, Prof. Dr. Bernd Fakler, and their team have elucidated the enormous spatial and temporal dynamics in protein composition of the AMPA-type glutamate receptors, the most important excitatory neurotransmitter receptors in the brain. These receptors are located in the synapses, the contact points between two nerve cells, where they are responsible for the rapid signal transduction and information processing. The results illustrate that the receptors are far more diverse than previously anticipated and pave the way for research into their functions in the various regions of the brain. The biologists published their findings in the journal Neuron.
The researchers have thus opened up the possibility to investigate the properties and functions of the AMPA receptors in the various regions of the brain at the level of their protein components. This is of particular significance as the AMPA receptors and their dynamics are regarded as central elements for memory formation. The researchers succeeded in elucidating the subunit structure of the AMPA receptors in various regions of the brain and even in different groups of distinct nerve cells. It became clear that the receptors exhibit an enormous range of variation in structure and molecular architecture and can evidently be precisely adapted to the function of the nerve cells and brain region in which they are located. In addition, the researchers demonstrated that this diversity in protein composition of the receptors is also exploited during the development of the brain.
In 2012, Fakler’s research team already used novel proteomic technologies to show that AMPA receptors in the brain are assembled from a pool of more than 30 different proteins - whose primary function(s) is are most parts as yet unknown. In fact in another recent study, also published in Neuron, the researchers demonstrated just how significant these unknown components are or can be: They showed that the cornichon protein dictates the time course of the AMPA receptor-mediated synaptic transmission and thus accounts for the difference between various types of nerve cells in the brain.
(Image caption: Granule cells connect with other cells via long projections (dendrites). The actual junctions (synapses) are located on thorn-like protuberances called “spines”. Spines are shown in green in the computer reconstruction. Credit: DZNE/Michaela Müller)
A protein couple controls flow of information into the brain’s memory center
Neuroscientists in Bonn and Heidelberg have succeeded in providing new insights into how the brain works. Researchers at the DZNE and the German Cancer Research Center (DKFZ) analyzed tissue samples from mice to identify how two specific proteins, ‘CKAMP44’ and ‘TARP Gamma-8’, act upon the brain’s memory center. These molecules, which have similar counterparts in humans, affect the connections between nerve cells and influence the transmission of nerve signals into the hippocampus, an area of the brain that plays a significant role in learning processes and the creation of memories. The results of the study have been published in the journal Neuron.
Brain function depends on the active communication between nerve cells, known as neurons. For this purpose, neurons are woven together into a dense network where they constantly relay signals to one another. However, neurons do not form direct contacts with each other. Instead they are separated by an extremely narrow gap, known as the synapse. This gap is bridged by ‘neurotransmitters’, which carry nerve signals from one cell to the next.
Docking stations
Specific molecular complexes in the cell’s outer shell, so-called ‘receptors’, receive the signal by binding the neurotransmitters. This triggers an electrical impulse in the receptor-bearing cell and thus the nerve signal has moved on one neuron further.
In the current study, a team led by Dr Jakob von Engelhardt focused on the AMPA receptors. These bind the neurotransmitter glutamate and are particularly common in the brain. “We looked at AMPA receptors in an area of the brain, which constitutes the main entrance to the hippocampus,” explains von Engelhardt, who works for the DZNE and DKFZ. “The hippocampus is responsible for learning and memory formation. Among other things it processes and combines sensory perception. We therefore asked ourselves how the flow of information into the hippocampus is controlled.”
A pair of helpers
Dr von Engelhardt’s research team specifically focused on two protein molecules: ‘CKAMP44’ and ‘TARP Gamma-8’. These proteins are present, along with AMPA receptors, in the ‘granule’ cells, which are neurons that receive signals from areas outside of the hippocampus. It was already known that these proteins form protein complexes with AMPA receptors. “We have now found out that they exert a significant influence on the functioning of glutamate receptors. Each in its own way, as chemically they are completely different,” says the neuroscientist. “We identified that the ability of a nerve cell to receive signals doesn’t depend solely on the actual receptors; CKAMP44 and TARP Gamma-8 are just as important. Their function cannot be separated from that of the receptors.”
This was the result of an analysis in which the researchers compared brain tissue from mice with a natural genotype with brain tissue from genetically modified mice. Neurons in the genetically modified animals were not able to produce either CKAMP44 or TARP Gamma-8 or both.
Long-term effect
The researchers discovered, among other things, that both proteins promote the transportation of glutamate receptors to the cell surface. “This means they influence how receptive the nerve cell is to incoming signals,” says von Engelhardt.
However, the number of receptors and thus the signal reception can be altered by neuronal activity. The von Engelhardt group found that in this regard the auxiliary molecules have different effects: TARP Gamma-8 is essential to ensure that more AMPA receptors are integrated into the synapse following a plasticity induction protocol, whereas CKAMP44 plays no role in this context. “Synapses alter their communication depending on their activity. This ability is called plasticity. Some of the changes involved are only temporary, others may last longer,” explains von Engelhardt. “TARP Gamma-8 influences long-term plasticity. It makes the cell able to strengthen synaptic communication for a prolonged time-period. The larger the number of receptors on the receiving side of the synapse, the better the neuronal connection.”
The number of receptors doesn’t change suddenly, but remains largely stable for a certain amount of time. “This condition may last for hours, days or even longer. This long-term effect is essential for the creation of memories. We can only remember things if the connections between neurons undergo a long-lasting change,” says the scientist.
Fast sequence of signals
However, CKAMP44 and TARP Gamma-8 also act over shorter periods of time. The research team discovered that the molecules affect how quickly the AMPA receptors return to a receptive state. “If glutamate has docked on to a receptor, it takes a while until the receptor can react to the next neurotransmitter. CKAMP44 lengthens this period. In contrast, TARP Gamma-8 helps the receptor to recover more quickly,” says von Engelhardt.
Hence, CKAMP44 temporarily weakens the synaptic connection, while TARP Gamma-8 strengthens it. Through the interplay of these proteins the synapse is able to tune its sensitivity to a specific level. This condition can last from milliseconds to a few seconds before the strength of the connection is again adapted. Specialists refer to this as “short-term plasticity”.
“These molecules ultimately influence how well the nerve cell is able to react to a rapid succession of signals,” the scientist summarises the findings. “Such a rapid firing enables neuronal networks to synchronize their activity, which is a common process in the brain.”
Sensitive balance
Much to the researchers’ surprise, it turned out that the two proteins influence not only the synapse but also the shape of the nerve cells. In the absence of these auxiliary molecules, the neurons have fewer dendrites to establish contact with other nerve cells. “The organism can use CKAMP44 and TARP Gamma-8 molecules to regulate neuronal connections in a number of ways,” von Engelhardt says. “This ability depends on the balance between the partners, as to some extent they have a contrary effect. The way in which the neurons of the hippocampus react to signals from other regions of the brain is therefore highly dependent on the presence and the expression ratio of these molecules.”
Since the two molecules act directly on the structure and function of synapses of granule cells, Jakob von Engelhardt considers it probable that they also have an influence on learning and memory.
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.