New Insight into Brain Stability: The Key Role of NMDA Receptors
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Research
Nov 14th, 2024
How Does the Brain Keep Calm?
- Biology
- Medicine
Researchers at Tel Aviv University have made a fundamental discovery: the NMDA receptor (NMDAR)—long studied primarily for its role in learning and memory—also plays a crucial role in stabilizing brain activity. By setting the “baseline” level for activity in neural networks, the NMDAR helps maintain stable brain function amidst continuous environmental and physiological changes. This discovery may lead to innovative treatments for diseases linked to disrupted neural stability, such as depression, Alzheimer’s disease, and epilepsy.
The study was led by Dr. Antonella Ruggiero, Leore Heim, and Dr. Lee Susman from Prof. Inna Slutsky’s lab at the Faculty of Medical and Health Sciences at Tel Aviv University. Prof. Slutsky, who is also affiliated with the Sagol School of Neuroscience, heads the Israeli Society for Neuroscience and directs the Sieratzki Institute for Advances in Neuroscience. Additional researchers included Dr. Ilana Shapira, Dima Hreaky, and Maxim Katsenelson from the Faculty of Medical and Health Sciences at Tel Aviv University, and Prof. Kobi Rosenblum from the University of Haifa. The study was published in the prestigious journal Neuron.
“In recent decades, brain research has mainly focused on processes that allow information encoding, memory, and learning, based on changes in synaptic connections between nerve cells”, says Prof. Slutsky.
“But the brain’s fundamental stability, or homeostasis, is essential to support these processes. In our lab, we explore the mechanisms that maintain this stability, and in this study, we focused on the NMDAR—a receptor known to play a role in learning and memory”, Slutsky continues.
This comprehensive project used three primary research methods: electrophysiological recordings from neurons in both cultured cells (in vitro) and living, behaving mice (in vivo) within the hippocampus, combined with computational modeling (in silico). Each approach provided unique insights into how NMDARs contribute to stability in neural networks.
Dr. Antonella Ruggiero studied NMDAR function in cultured neurons using an innovative technique called “dual perturbation”, developed in Prof. Slutsky’s lab. “First, I exposed neurons to ketamine, a known NMDAR blocker”, she explains. “Typically, neuronal networks recover on their own after disruptions, with activity levels gradually returning to baseline due to active compensatory mechanisms. But when the NMDAR was blocked, activity levels stayed low and didn’t recover. Then, with the NMDAR still blocked, I introduced a second perturbation by blocking another receptor. This time, the activity dropped and recovered as expected, but to a new, lower baseline set by ketamine, not the original level”. This finding reveals the NMDAR as a critical factor in setting and maintaining the activity baseline in neuronal networks. It suggests that NMDAR blockers may impact behavior not only through synaptic plasticity but also by altering homeostatic set points.
Building on this discovery, Dr. Ruggiero sought to uncover the molecular mechanisms behind the NMDAR’s role in tuning the set point. She identified that NMDAR activity enables calcium ions to activate a signaling pathway called eEF2K-BDNF, previously linked to ketamine’s antidepressant effects.
How NMDARs Set the Brain’s Activity Baseline
Leore Heim investigated whether the NMDAR similarly affects baseline activity in the hippocampus of living animals. A major technical challenge was administering an NMDAR blocker directly to the hippocampus without affecting other brain areas, while recording long-term activity at the individual neuron level. “Previous studies often used injections that delivered NMDAR blockers across the entire brain, leading to variable and sometimes contradictory findings,” he explains. “To address this, I developed a method combining direct drug infusion into the hippocampus with long-term neural activity recording in the same region. This technique revealed a consistent decrease in hippocampal activity across states like wakefulness and sleep, with no compensatory recovery as seen with other drugs. This strongly supports that NMDARs set the activity baseline in hippocampal networks in living animals”.
Mathematician Dr. Lee Susman created computational models to answer a longstanding question: Is brain stability maintained at the level of the entire neural network, or does each neuron individually stabilize itself? “Based on the data from Antonella and Leore’s experiments, I found that stability is maintained at the network level, not within single neurons,” he explains. “Using models of neural networks, I showed that averaging activity across many neurons provides computational benefits, including noise reduction and enhanced signal propagation. However, we need to better understand the functional significance of single-neuron drift in future studies”.
Prof. Slutsky adds: “We know that ketamine blocks NMDARs, and in 2008, it was FDA-approved as a rapid-acting treatment for depression. Unlike typical antidepressants like Cipralex and Prozac, ketamine acts immediately by blocking NMDARs. However, until now, it wasn’t fully understood how the drug produced its antidepressant effects. Our findings suggest that ketamine’s actions may stem from this newly discovered role of NMDAR: reducing the activity baseline in overactive brain regions seen in depression, like the lateral habenula, without interfering with homeostatic processes. This discovery could reshape our understanding of depression and pave the way for developing innovative treatments".
Research
Nov 14th, 2024
Is There a Way to Stop Parkinson’s Disease at Its Source?
TAU Researchers discovered a potential new target for developing effective treatments for Parkinson's disease.
- Medicine
Researchers at Tel Aviv University discovered a new factor in the pathology of Parkinson's disease, which in the future may serve as a target for developing new treatments for this terrible ailment, affecting close to 10 million people worldwide.
The researchers: "We found that a variant of the TMEM16F protein, caused by a genetic mutation, enhances the spread of Parkinson's pathology through nerve cells in the brain".
The study was led by Dr. Avraham Ashkenazi and PhD student Stav Cohen Adiv Mordechai from the Department of Cell and Developmental Biology at TAU's Faculty of Medical and Health Sciences and the Sagol School of Neuroscience. Other contributors included: Dr. Orly Goldstein, Prof. Avi Orr-Urtreger, Prof. Tanya Gurevich and Prof. Nir Giladi from TAU's Faculty of Medical and Health Sciences and the Tel Aviv Sourasky Medical Center, as well as other researchers from TAU and the University of Haifa. The study was backed by the Aufzien Family Center for the Prevention and Treatment of Parkinson's Disease at TAU. The paper was published in the scientific journal Aging Cell.
Doctoral student Stav Cohen Adiv Mordechai explains: "A key mechanism of Parkinson's disease is the aggregation in brain cells of the protein α-synuclein (in the form of Lewy bodies), eventually killing these cells. For many years, researchers have tried to discover how the pathological version of α-synuclein spreads through the brain, affecting one cell after another, and gradually destroying whole brain sections. Since α-synuclein needs to cross the cell membrane to spread, we focused on the protein TMEM16F, a regulator situated in the cell membrane, as a possible driver of this lethal process".
α-synuclein spread in the mouse brain.
At first, the researchers genetically engineered a mouse model without the TMEM16F gene, and derived neurons from the brains of these mice for an in-vitro cellular model. Using a specially engineered virus, they caused these neurons to express the defective α-synuclein associated with Parkinson's and compared the results with outcomes from normal brain cells containing TMEM16F. They found that when the TMEM16F gene had been deleted, the α-synuclein pathology spread to fewer healthy neighboring cells compared to the spread from normal cells. The results were validated in-vivo in a living mouse model of Parkinson's disease.
TMEM16F Mutation Linked to Parkinson’s Risk in Ashkenazi Jews
In addition, in collaboration with the Neurological Institute at the Tel Aviv Sourasky Medical Center, the researchers looked for mutations (variants) in the TMEM16F gene that might increase the risk for Parkinson's disease. Dr. Ashkenazi explains: "The incidence of Parkinson's among Ashkenazi Jews is known to be relatively high, and the Institute conducts a vast ongoing genetic study on Ashkenazi Jews who carry genes increasing the risk for the disease. With their help, we were able to identify a specific TMEM16F mutation which is common in Ashkenazi Jews in general, and in Ashkenazi Parkinson's patients in particular". Cells carrying the mutation were found to secrete more pathological α-synuclein compared to cells with the normal gene. The researchers explain that the mechanism behind increased secretion has to do with the biological function of the TMEM16F protein: the mutation increases the activity of TMEM16F, thereby affecting membrane secretion processes.
Stav Cohen Adiv Mordechai: "In our study, we discovered a new factor underlying Parkinson's disease: the protein TMEM16F, which mediates secretion of the pathological α-synuclein protein through the cell membrane to the cell environment. Picked up by healthy neurons nearby, the defective α-synuclein forms Lewy bodies inside them, and gradually spreads through the brain, damaging more and more brain cells. Our findings mark TMEM16F as a possible new target for the development of effective treatments for Parkinson's disease. If, by inhibiting TMEM16F, we can stop or reduce the secretion of defective α-synuclein from brain cells, we may be able to slow down or even halt the spread of the disease through the brain".
Dr. Ashkenazi emphasizes that research on the new Parkinson's mechanism has only begun, and quite a number of questions still remain to be explored: Does inhibiting TMEM16F actually reduce the symptoms of Parkinson's disease? Does the lipid composition of cell membranes play a part in spreading the disease in the brain? Is there a link between mutations in TMEM16F and the prevalence of Parkinson's in the population? The research team intends to continue the investigation in these directions and more.
Research
Nov 11th, 2024
Can Smartphones Help Prevent Wildfires?
New research reveals the untapped power of mobile sensors.
- Environment
A new study from Tel Aviv University has found that the smartphones we all carry in our pockets could help collect weather data from the public to provide early warnings for extreme weather, such as wildfires.
Your Phone Could Help Prevent Natural Disasters
The researchers explain that all smartphones are equipped with multiple micro-sensors capable of collecting important environmental data, such as temperature, barometric pressure, humidity, magnetic field, light, sound, location, acceleration, gravity, and more. These data help us find our way or define our location, they warn us when the battery overheats or the device absorbs moisture - all in real-time, without saving the data. The researchers demonstrated that smart use of such data could support early warnings for severe wildfire events, especially since millions or even billions of data points are collected worldwide every day by our smartphones. Today, early warning systems in remote forested areas typically lack data due to the absence of weather stations in remote locations. The public, however, takes their smartphones everywhere, with each phone containing sophisticated micro-sensors that operate continuously in the background, but these data are normally lost and not saved. However, many companies have started to collect smartphone data to use for various purposes, with user consent. The researchers believe that this huge data source (as of 2024, there are over 7 billion smartphones worldwide) could aid in forecasting extreme weather and natural disasters.
Prof. Colin Price and PhD student Hofit Shachaf from the Department of Geophysics in the Porter School of the Environment and Earth Sciences at Tel Aviv University used data collected from the global public via the WeatherSignal app (OpenSignal) to develop a methodology for assessing wildfire risk based solely on smartphone data collected by the public. The results were recently published in the journal Natural Hazards and Earth System Sciences (NHESS).
Prof. Colin Price.
One key parameter determining the likelihood of a wildfire is the moisture content in vegetation (essentially the fuel available for the fire) - which, in turn, is determined by the temperature and relative humidity of the surrounding air. Both temperature and relative humidity can be easily obtained from the public's smartphones.
Hofit Shachaf explains: “We developed an index based on VPD (vapor pressure deficit), which reflects the dryness of the vegetation based on environmental parameters (temperature and humidity). In hot and dry atmospheric conditions more moisture is drawn from the plants, due to enhanced evaporation and transpiration (evapotranspiration) that essentially facilitates ignition of fires. In cooler, more humid air, forests do not usually catch fire since their moisture level is too high. Previous studies have also used VPD to predict wildfire risk levels - though the data for these calculations is mostly obtained from local weather stations. The novelty of our study is the utilization of data collected from smartphones, without their users' active participation, to calculate VPD over large areas and at high spatial and temporal resolutions - providing important insights into wildfire risk evaluation”.
Fixing Smartphone Data to Predict Wildfires
However, smartphone data do contain errors. The temperature reading might reflect the air conditioning in your office, while the humidity sensor might identify moisture when the user is taking a shower. However, the huge amount of data collected from smartphones allows us to remove outliers in the data set. Furthermore, since the micro-sensors are not calibrated before they are put in our phones, it was necessary first to calibrate the local smartphone data against commercial meteorological stations. This procedure turned out to be relatively straightforward, with just a single calibration needed to correct a smartphone's readings. After calibrating or “training” the device, the researchers analyzed two major wildfire events: fires in Israel in November 2016 and the massive fire in Portugal in July 2013. The results were surprising, with smartphone data collected from the public showing significant VPD anomalies before and during these major fires.
Hofit Shachaf adds: “It’s surprising, but even though each smartphone has its errors and biases, with large amounts of data from many smartphones, we can average out the errors and still retain useful data. The large volume of data helps overcome issues associated with individual smartphones”.
Global smartphone coverage has increased by about 30% in the last five years. As their global density continues to grow, data collected from smartphones could eventually offer better spatial resolution than traditional meteorological networks - especially in urban areas where natural disasters like fires and floods, can have a significant impact. Moreover, in low-income countries lacking meteorological infrastructures, smartphones could provide useful data for monitoring extreme weather conditions.
Prof. Price concludes: “Given the rapid increase in smartphones worldwide, we propose utilizing this data source to provide better early warnings to the public and disaster managers about impending natural disasters. Better early warnings could prevent natural hazards from becoming natural disasters”.
Research
Nov 10th, 2024
Buzzed but Never Tipsy: Hornets’ Remarkable Alcohol Tolerance
Oriental hornets are the only animals able to drink unlimited amounts of alcohol.
- Biology
A new study from the School of Zoology and the Steinhardt Museum of Natural History at Tel Aviv University has revealed that the Oriental hornet is the only known animal capable of chronically consuming alcohol in high concentrations with almost no negative effects on its health or lifespan. The research team says, "This is a remarkable animal that shows no signs of intoxication or illness even after ingesting huge amounts of alcohol."
The research was conducted under the leadership of postdoctoral fellow Dr. Sofia Bouchebti from Prof. Eran Levin's laboratory at Tel Aviv University’s School of Zoology and the Steinhardt Museum of Natural History. The study was published in the journal Proceedings of the National Academy of Sciences of the United States of America (PNAS).
The researchers explain that alcohol is commonly produced in nature through the breakdown of sugars by yeasts and bacteria, primarily found in ripe fruits and nectar. Although alcohol contains nearly twice the amount of energy as sugar, it is toxic to most animals — including us humans — with occasional consumption, and especially with chronic use. Among the animals known to consume alcohol are fruit flies, which show signs of alcohol poisoning even at relatively low concentrations, and treeshrews — mammals native to East Asia that feed on ripe, alcohol-rich fruits — who show symptoms such as fatty liver and other effects indicative of alcoholism after consuming low concentrations of alcohol continuously for several days.
As for humans, many of us like consuming alcohol. Humans domesticated the wine grape around 10,000 years ago, and compared to other animals, we can tolerate and often enjoy consuming relatively high amounts of alcohol. However, as we know, alcohol has significant effects on behavior, cognition, and, of course, health, with a host of diseases linked to its consumption.
Hornets Can Handle Their Liquor
In the new study, the research team tested the Oriental hornet’s ability to consume alcohol and break it down. Dr. Bouchebti explains: "The hornets naturally store yeasts in their digestive system, which provides them with a unique environment that allows the yeast to develop and reproduce, creating new strains. One explanation is that hornets transfer yeasts to fruits, which indirectly contributes to the production of wine. In our study, we labeled the alcohol consumed by the hornets with a heavy carbon isotope. As the alcohol is metabolized, it breaks down into carbon dioxide, which is exhaled. By measuring the amount of labeled carbon dioxide emitted, we were able to estimate the speed at which the alcohol was broken down. The findings were surprising; we were amazed to see the rapid rate at which the hornets metabolized the alcohol".
In the next stage, the researchers sought to determine whether the Oriental hornet ever becomes intoxicated. Does increased alcohol consumption affect their behavior, for example causing aggression or impacting their nest-building abilities? Here too, the findings were surprising: even when consuming high concentrations of alcohol (80 percent alcohol as the sole source of nutrition) there was no noticeable effect on the hornets’ behavior. In the final phase of the study, the researchers tested whether alcohol had any impact on the hornets’ lifespan and health. Once again, they were amazed to discover that no differences were found between the lifespan of hornets that consumed only alcohol for their entire lives (three months) and hornets that consumed sugar water.
No Hangovers Here
Prof. Levin concludes: "To the best of our knowledge, Oriental hornets are the only animal adapted to consuming alcohol as a metabolic fuel. They show no signs of intoxication or illness, even after chronically consuming huge amounts of alcohol, and they eliminate it from their bodies very quickly. In a bioinformatics analysis of the Oriental hornet’s genome, conducted by Prof. Dorothee Huchon, it was discovered that the hornet possesses several copies of the gene responsible for producing the enzyme that breaks down alcohol; this genetic adaptation may be related to their incredible ability to handle alcohol. We propose that the ancient relationship between hornets and yeast led to the development of this adaptation. Furthermore, while alcohol-related research is highly advanced, with 5.3 percent of deaths in the world linked to alcohol consumption, we believe that, following our research, Oriental hornets could potentially be used to develop new models for studying alcoholism and the metabolism of alcohol".
Research
Nov 3rd, 2024
TAU Breakthrough Reveals Mechanism That Eliminates Tumors
Researchers identified a mechanism that eliminates tumors—even those resistant to immunotherapy.
- Medicine
A technological breakthrough by medical researchers at Tel Aviv University enabled the discovery of a cancer mechanism that prevents the immune system from attacking tumors. The researchers were surprised to find that reversing this mechanism stimulates the immune system to fight the cancer cells, even in types of cancer considered resistant to prevailing forms of immunotherapy. The breakthrough was led by Prof. Carmit Levy, Prof. Yaron Carmi, and PhD student Avishai Maliah from TAU's Faculty of Medical and Health Sciences. The paper was published in the leading journal Nature Communications.
Prof. Levy: "It all happened by coincidence. My lab studies both cancer and the effects of ultraviolet (UV) radiation from the sun on our skin and body – both of which are known to suppress the immune system. Cancer suppresses approaching immune cells and solar radiation suppresses the skin's immune system. While in most cases, we cancer researchers worldwide focus on the tumor and look for mechanisms by which cancer inhibits the immune system, here we proposed a different approach: investigating how UV exposure suppresses the immune system and applying our findings to cancer. The discovery of a mechanism that inhibits the immune system opens new paths for innovative therapies".
What Surprising Findings Emerged from the Research?
Prof. Levy adds: "With this idea in mind, I asked my colleague Prof. Yaron Carmi, a global expert on the immune system, to join the study. Avishai Maliah, an MD/PhD candidate in my lab, led the project. The first stage was a comprehensive investigation of changes in the skin induced by exposure to UV, using a mouse model. Avishai examined the behavior of dozens of proteins post-UV exposure and surprisingly discovered a significant rise in the level of a relatively unexplored protein called Ly6a. This unexpected finding led us to investigate further, to understand the protein function and whether it is involved in the immune suppression process".
Prof. Carmi explains: "It's important to understand a basic aspect of the immune system's function. Our natural immune system is very efficient and very powerful, but it contains quite a few brakes and controls, to prevent overactivity that can cause autoimmune diseases – in which the body attacks itself. When our skin is exposed to UV radiation from the sun, our immune system responds immediately: blood vessels expand, DNA is repaired wherever possible, and cells with mutations are identified and removed. At the same time, a strong control system with numerous brakes is also activated to prevent overactivity".
How Does UV Exposure Affect Immune Response?
Prof. Levy: "The use of sunlight to suppress autoimmune diseases of the skin – when the skin's immune system overreacts - has been known for years. Phototherapy is basically the application of UV radiation to treat patients with autoimmune diseases, such as psoriasis, vitiligo and more, because ultimately UV suppresses the skin's immune system".
Avishai Maliah: "We found that after exposure to UV radiation, the immune system's T cells - that play a critical role in fighting cancer - begin to express high levels of the protein Ly6a. We suspected that Ly6a serves as a brake through which UV inhibits the immune system, and that by releasing this brake, optimal activation of the immune system might be resumed".
Prof. Levy: "We were surprised to discover that this protein, Ly6a, is also overexpressed in cancer tumors – apparently inhibiting T cells. Having found this in two types of cancer, melanoma skin cancer and colon cancer, we have reason to believe that the same thing happens in other cancers as well. Evidently, we have discovered a general mechanism through which cancer tumors desensitize the immune system. Avishai treated cancer with Ly6a antibodies, and amazingly the tumors were significantly reduced. Moreover, cancers resistant to known treatments reacted substantially to Ly6a antibodies". The new discovery can have practical implications in immunotherapy – treating cancer by enhancing the response of the immune system.
Prof. Carmi: "Immunotherapy has revolutionized the treatment of cancer. However, about 50% of the patients do not respond to the currently prevailing treatment – the protein PD1. We discovered a new protein, Ly6a, and found that its antibody eradicated tumors in our model animals - even those resistant to PD1 therapy. We are currently working to translate our findings into a drug for human cancer patients, hoping to offer an effective new treatment".
