Study links brain stability to treatments for depression, epilepsy and Alzheimer’s
New scientific research on how the brain maintains stability amidst continuous environmental and physiological changes offers potential new approaches to treat disorders such as depression, Alzheimer’s disease, and epilepsy, Israeli researchers said on Thursday.
Tel Aviv University on Aug. 20, 2024. Photo by Yossi Zeliger/TPS-IL
For decades, research has concentrated on how the brain learns and remembers—processes dependent on changes in synaptic connections. However, a Tel Aviv University study found that homeostasis — the brain’s stability — is a foundation for all cognitive functions. Without this stability, processes like learning, memory, and even basic neural communication could falter.
“While brain research has historically focused on synaptic changes that underpin learning and memory, the fundamental stability—or homeostasis—of the brain is equally critical,” said Tel Aviv University Prof. Inna Slutsky Slutsky, in whose laboratory investigated the mechanisms that maintain this balance.
Depression, epilepsy, Alzheimer’s disease, and other disorders are linked to disruptions in neural stability.
The study, published in the peer-reviewed journal, Neuron, zeroed in on NMDA receptors (NMDARs), a type of glutamate receptor found in the brain and nervous system. They play a key role in synaptic transmission, plasticity, and the regulation of neural activity.
The research employed three complementary methods: electrophysiological recordings from cultured neurons and living mice, coupled with computational modeling. This comprehensive approach provided a deep understanding of how NMDARs stabilize neural networks.
Dr. Antonella Ruggiero, one of the research leaders, utilized an innovative “dual perturbation” technique developed in Slutsky’s lab. Initially, neurons were exposed to ketamine, a known NMDAR blocker. Under normal conditions, neural networks recover from disruptions, gradually returning to baseline activity levels. However, with NMDAR blocked, the recovery failed, and activity levels remained suppressed.
Subsequently, a second disruption was introduced by blocking another receptor. This time, activity recovered but to a new, lower baseline, highlighting NMDAR’s role in setting and maintaining the activity baseline.
“These findings suggest that NMDAR blockers like ketamine impact behavior not only through synaptic plasticity but also by altering the brain’s homeostatic set points,” Ruggiero explained.
Further experiments revealed that NMDAR activity activates a calcium-dependent signaling pathway, eEF2K-BDNF, linked to ketamine’s antidepressant effects.
Co-leader Leore Heim extended these findings to live animals, focusing on the hippocampus, a brain region critical for memory and learning. By infusing NMDAR blockers directly into the hippocampus and recording long-term neural activity, Heim observed a consistent decrease in activity across various states, such as wakefulness and sleep.
“This method allowed us to isolate the hippocampus, avoiding the variability seen in previous studies where drugs were administered systemically,” said Heim. “Our results demonstrate that NMDARs set the activity baseline in hippocampal networks, with no compensatory recovery after their inhibition.”
To understand whether brain stability occurs at the network or individual neuron level, co-leader Dr. Lee Susman developed computational models. His findings indicated that stability is achieved through network-level mechanisms, where averaging activity across neurons reduces noise and enhances signal processing.
“While individual neurons exhibit activity drift, the overall network maintains stability, providing significant computational benefits,” Susman said.
The study’s findings could open new avenues of treatment for depression, epilepsy, and Alzheimer’s. Ketamine, which blocks NMDARs, was FDA-approved in 2008 as a rapid-acting antidepressant.
Overactivity in certain brain regions, such as the lateral habenula, contributes to depression. The study suggests that ketamine could help by resetting this overactivity to a healthier baseline. Understanding how NMDARs stabilize neural networks could lead to treatments preventing epileptic episodes. And targeting NMDARs could help maintain brain function as Alzheimer’s progresses.
“This could pave the way for novel treatments that target neural stability without disrupting essential homeostatic processes,” said Slutsky.
