Researchers at Tel Aviv University (TAU) have determined that the NMDA receptor (NMDAR) in the brain, 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 of Professor Inna Slutsky’s lab at TAU’s Faculty of Medical and Health Sciences. Professor Slutsky, who is also affiliated with TAU’s Sagol School of Neuroscience, heads the Israeli Society for Neuroscience and directs the Sieratzki Institute for Advances in Neuroscience. The study was published on November 7, 2024, in the 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 Professor 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.”

This comprehensive project used 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. Ruggiero studied NMDAR function in cultured neurons using an innovative technique called “dual perturbation,” developed in Professor 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 revealed 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 determined that NMDAR activity enables calcium ions to activate a signaling pathway called eEF2K-BDNF, previously linked to ketamine’s antidepressant effects.

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,” Heim 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.”

Dr. Susman, a mathematician, 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,” Dr. Susman says. “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.”

“We know that ketamine blocks NMDARs, and in 2008, it was FDA-approved as a rapid-acting treatment for depression,” Professor Slutsky says. “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.”

Additional researchers included Dr. Ilana Shapira, Dima Hreaky, and Maxim Katsenelson from TAU’s Faculty of Medical and Health Sciences, and Professor Kobi Rosenblum of the University of Haifa.