Researchers from Tel Aviv University have made a fundamental discovery: the NMDA receptor (NMDAR) – long studied mainly for its role in learning and memory – also plays a crucial role in stabilizing brain activity. By setting the “baseline” level of activity in neural networks, the NMDAR helps maintain stable brain function amid ongoing environmental and physiological changes. This discovery could lead to innovative treatments for diseases associated with 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 the laboratory of Prof. Inna Slutsky at Tel Aviv University’s Faculty of Medical and Health Sciences. Prof. Slutsky, who is also affiliated with the Sagol School of Neuroscience, directs the Israeli Society for Neuroscience and directs the Sieratzki Institute for Advances in Neuroscience. Other researchers included Dr. Ilana Shapira, Dima Hreaky and Maxim Katsenelson from Tel Aviv University’s Faculty of Medical and Health Sciences, and Prof. Kobi Rosenblum from the University of Haifa. The study was published in the prestigious journal Neuron.
In recent decades, brain research has focused on processes that enable information encoding, memory and learning, based on changes in synaptic connections between nerve cells. But the brain’s fundamental stability, or homeostasis, is essential to support these processes. In our laboratory we investigate the mechanisms that maintain this stability, and in this study we focused on the NMDAR receptor, which is known to play a role in learning and memory.”
Prof. Inna Slutsky, Faculty of Medical and Health Sciences at Tel Aviv University
This comprehensive project used three primary research methods: electrophysiological recordings from neurons in both cultured cells (in vitro) and live, 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 ‘double disruption’, developed in Prof. Slutsky’s laboratory. “First I exposed neurons to ketamine, a known NMDAR blocker,” she explains. ‘Normally, neuronal networks recover naturally after perturbations, with activity levels gradually returning to baseline as a result of active compensatory mechanisms. But when the NMDAR was blocked, activity levels remained low and did not recover. When the NMDAR was still blocked, I introduced a second disruption by blocking another receptor. This time, activity dropped and recovered as expected, but to a new, lower baseline determined by ketamine, not the original level.” This finding reveals that the NMDAR is a critical factor in establishing and maintaining the activity baseline in neuronal networks. It suggests that NMDAR blockers may influence behavior not only through synaptic plasticity, but also by altering homeostatic set points.
Building on this discovery, Dr. Ruggiero to uncover the molecular mechanisms behind the role of the NMDAR in set point tuning. She identified that NMDAR activity allows calcium ions to activate a signaling pathway called eEF2K-BDNF, which has previously been linked to the antidepressant effects of ketamine.
Leore Heim investigated whether the NMDAR influences basic activity in the hippocampus of living animals in a similar way. A major technical challenge was delivering an NMDAR blocker directly to the hippocampus without affecting other brain regions, while recording long-term activity at the individual neuron level. “Previous studies often used injections that delivered NMDAR blockers throughout the brain, leading to variable and sometimes conflicting findings,” he explains. “To address this, I developed a method that combines direct drug infusion into the hippocampus with long-term recording of neural activity in the same region. This technique revealed a consistent decrease in hippocampal activity across different states such as wakefulness and sleep, without compensatory recovery with other drugs strongly supports the fact that NMDARs determine the activity baseline in hippocampal networks in living animals.”
Mathematician Dr. Lee Susman created computer models to answer a long-standing question: Is brain stability maintained at the level of the entire neural network, or does each neuron stabilize itself individually? “Based on the data from Antonella and Leore’s experiments, I found that stability is maintained at the network level, and not within individual neurons,” he explains. “Using neural network models, I showed that averaging activity across many neurons provides computational benefits, including noise reduction and improved 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 approved by the FDA as a fast-acting treatment for depression. Unlike typical antidepressants like Cipralex and Prozac, ketamine works immediately by blocking NMDARs. So far, however, ketamine works immediately. Our findings suggest that ketamine’s action may stem from this newly discovered role of NMDAR: reducing baseline activity in overactive brain areas seen in depression, such as the lateral habenula, without disrupting homeostatic processes. This discovery could reshape our understanding of depression and pave the way for developing innovative treatments.
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Magazine reference:
Ruggiero, A., et al. (2024). NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics. Neuron. doi.org/10.1016/j.neuron.2024.10.014.