Posts tagged granule cells
Articles and news from the latest research reports.
(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.
Scientists find new clues to brain’s wiring
New research provides an intriguing glimpse into the processes that establish connections between nerve cells in the brain. These connections, or synapses, allow nerve cells to transmit and process information involved in thinking and moving the body.
Reporting online in Neuron, researchers at Washington University School of Medicine in St. Louis have identified a group of proteins that program a common type of brain nerve cell to connect with another type of nerve cell in the brain.
The finding is an important step forward in efforts to learn how the developing brain is built, an area of research essential to understanding the causes of intellectual disability and autism.
“We now are looking at how loss of this wiring affects brain function in mice,” said senior author Azad Bonni, MD, PhD, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology at the School of Medicine.
Bonni and his colleagues are studying synapses in the cerebellum, a region of the brain that sits in the back of the head. The cerebellum plays a central role in controlling the coordination of movement and is essential for what researchers call procedural motor learning, which makes it possible to move our muscles at an unconscious level, such as when we ride a bicycle or play the piano.
“The cerebellum also regulates mental functions,” Bonni said. “So, impairment of the wiring of nerve cells in the cerebellum may contribute to movement disorders as well as cognitive problems including autism spectrum disorders.”
His new results show that a complex of proteins known as NuRD (nucleosome remodeling and deacetylase) plays a fairly high supervisory role in some aspects of the cerebellum’s construction. When the researchers blocked the NuRD complex, cells in the cerebellum called granule cells failed to form connections with other nerve cells, the Purkinje neurons. These circuits are important for the cerebellum’s control of movement coordination and learning.
Bonni and his colleagues showed that NuRD exerts influence at the epigenetic level, which means it controls factors other than DNA that affect gene activity. For example, NuRD affects the configurations of molecules that store DNA and that can open and close the coils of DNA like an accordion, making genes less or more accessible. Changing the accessibility of genes changes their activity levels. For instance, cells can’t frequently make proteins from genes in a tightly packed coil of DNA.
NuRD also alters tags on the proteins that store DNA, decreasing the chances that the gene will be used. Among the genes deactivated by NuRD are two that control the activity of other genes involved in the wiring of the cerebellum.
“This tells us that the NuRD complex is very influential—not only does it affect the activity of genes directly, it also controls other regulators of multiple genes,” Bonni said.
(Image: Courtesy of VJ Wedeen and LL Wald, Martinos Center, Harvard Medical School, Human Connectome Project)
Research reveals first glimpse of a brain circuit that helps experience to shape perception
Odors have a way of connecting us with moments buried deep in our past. Maybe it is a whiff of your grandmother’s perfume that transports you back decades. With that single breath, you are suddenly in her living room, listening as the adults banter about politics. The experiences that we accumulate throughout life build expectations that are associated with different scents. These expectations are known to influence how the brain uses and stores sensory information. But researchers have long wondered how the process works in reverse: how do our memories shape the way sensory information is collected?
In work published today in Nature Neuroscience, scientists from Cold Spring Harbor Laboratory (CSHL) demonstrate for the first time a way to observe this process in awake animals. The team, led by Assistant Professor Stephen Shea, was able to measure the activity of a group of inhibitory neurons that links the odor-sensing area of the brain with brain areas responsible for thought and cognition. This connection provides feedback so that memories and experiences can alter the way smells are interpreted.
The inhibitory neurons that forget the link are known as granule cells. They are found in the core of the olfactory bulb, the area of the mouse brain responsible for receiving odor information from the nose. Granule cells in the olfactory bulb receive inputs from areas deep within the brain involved in memory formation and cognition. Despite their importance, it has been almost impossible to collect information about how granule cells function. They are extremely small and, in the past, scientists have only been able to measure their activity in anesthetized animals. But the animal must be awake and conscious in order to for experiences to alter sensory interpretation. Shea worked with lead authors on the study, Brittany Cazakoff, graduate student in CSHL’s Watson School of Biological Sciences, and Billy Lau, Ph.D., a postdoctoral fellow. They engineered a system to observe granule cells for the first time in awake animals.
Granule cells relay the information they receive from neurons involved in memory and cognition back to the olfactory bulb. There, the granule cells inhibit the neurons that receive sensory inputs. In this way, “the granule cells provide a way for the brain to ‘talk’ to the sensory information as it comes in,” explains Shea. “You can think of these cells as conduits which allow experiences to shape incoming data.”
Why might an animal want to inhibit or block out specific parts of a stimulus, like an odor? Every scent is made up of hundreds of different chemicals, and “granule cells might help animals to emphasize the important components of complex mixtures,” says Shea. For example, an animal might have learned through experience to associate a particular scent, such as a predator’s urine, with danger. But each encounter with the smell is likely to be different. Maybe it is mixed with the smell of pine on one occasion and seawater on another. Granule cells provide the brain with an opportunity to filter away the less important odors and to focus sensory neurons only on the salient part of the stimulus.
Now that it is possible to measure the activity of granule cells in awake animals, Shea and his team are eager to look at how sensory information changes when the expectations and memories associated with an odor change. “The interplay between a stimulus and our expectations is truly the merger of ourselves with the world. It exciting to see just how the brain mediates that interaction,” says Shea.
Analysis of 26 networked autism genes suggests functional role in the cerebellum
A team of scientists has obtained intriguing insights into two groups of autism candidate genes in the mammalian brain that new evidence suggests are functionally and spatially related. The newly published analysis identifies two networked groupings from 26 genes associated with autism that are overexpressed in the cerebellar cortex, in areas dominated by neurons called granule cells.
The team, composed of neuroscientists and computational biologists, worked from a database providing expression levels of individual genes throughout the mouse brain, as complied in the open-source Allen Mouse Brain Atlas. To promote reproducibility, the scientists surveyed expression data of over 3000 genes, about three-fourths of all the genes listed in the Atlas for which two independent sets of data have been complied.
The work was led by Professor Partha Mitra of Cold Spring Harbor Laboratory (CSHL) and scientists from MindSpec, a nonprofit research organization, founded by Dr. Sharmila Banerjee-Basu.
Despite obvious genetic and neuroanatomical differences between mouse and human, the team explains, mouse models are extremely effective in dissecting out the role of specific genes, pathways, neuronal subtypes and brain regions in specific abnormal behaviors manifested in both mice and people.
Based on years of studies in both species, scientists now know of mutations affecting more than 300 genes whose occurrence correlates with autism susceptibility; more are certain to be identified. Some of these candidate genes are more strongly correlated with the illness than others, although correlation is not the same thing as direct evidence of causation.
Nevertheless, “the key question as yet unanswered,” notes Dr. Mitra, “concerns the way or ways in which particular mutations, singly or in combination, cause pathologies that result in the complex combination of symptoms that characterizes autism in children.” It is assumed that autism pathologies are the result of insults — genetic, environmental, or most likely both — sustained at the time of conception and early in development.
Dr. Idan Menashe, now of Ben-Gurion University of the Negev in Israel, and Dr. Pascal Grange, a postdoctoral researcher in the Mitra lab, demonstrated that co-expression of 26 autism genes was “significantly higher” than would occur by chance. “This suggests that these 26 genes have common neuro-functional properties,” says Dr. Menashe.
The team found two co-expressed networks or “cliques” of genes that are significantly enriched with autism genes. They then asked where in the mouse brain these cliques are expressed. Notably, genes in both groups showed significant overexpression in the cerebellar cortex, and particularly in regions in which granule cells predominate. “This result supports prior studies pointing to involvement of the cerebellum in autism,” says Dr. Grange. Specifically, a recent neuroimaging study highlighted functional subregions in the cerebellum as playing a role in both motor and cognitive tasks. Other genes associated with autism have been shown in other studies to play a role in the development of this brain region.
“Our study provides insights into co-expression properties of genes associated with autism and suggests specific brain regions implicated in pathology. Complementing these findings with additional genomic and neuroimaging analyses from both mouse and human brains will help in obtaining a broader picture of the autistic brain,” the team concludes.
Some brain cells are better virus fighters
Viruses often spread through the brain in patchwork patterns, infecting some cells but missing others. New research at Washington University School of Medicine in St. Louis helps explain why. The scientists showed that natural immune defenses that resist viral infection are turned on in some brain cells but switched off in others.
“The cells that a pathogen infects can be a major determinant of the seriousness of brain infections,” says senior author Michael Diamond, MD, PhD, professor of medicine. “To understand the basis of disease, it is important to understand which brain regions are more susceptible and why.”
While some brain infections are caused by bacteria, fungi or parasites, often the cause is a virus, such as West Nile virus, herpesvirus or enteroviruses.
For their study, now available online in Nature Medicine, the researchers focused on granule cell neurons, a cell type that rarely becomes infected. They compared gene profiles in granule cells from the cerebellum with the activity in cortical neurons in the cerebral cortex, which are more vulnerable to infection.
The comparison revealed many differences, including a number of genes in cortical neurons that were less well-expressed—meaning that for those specific genes there were fewer copies of mRNA, the molecules that relay genetic information from DNA to the cell’s protein-making mechanisms.
Next, the researchers transferred individually 40 of those genes into cortical neurons and screened the cells for susceptibility to viral infection. The test highlighted three antiviral genes that are induced by interferon, an important immune system protein. When the expression level of these genes increased in cortical neurons, the cells’ susceptibility to viral infection decreased.
The researchers also identified mechanisms that make some of these changes in genetic programming happen: regulatory factors known as microRNA, and differences in the way DNA is modified in the cell nucleus, both of which can affect gene expression levels.
Some of the genetic changes are only helpful against specific viral families, while others are effective against a broader spectrum of viruses and bacteria. The scientists can’t say yet if the differences in infection susceptibility are driven by the need to prevent infection or if they are a byproduct of changes that help neurons in particular brain regions perform essential functions.
To learn more about how these innate immune genes help cells resist infection, Diamond and his colleagues are disabling them in the brains of mice.