Experiments with neural network cultures and mice have shown that even when NMDARs are blocked, the overall activity of neural networks remains at a new equilibrium point. These findings shed light on the unique role of NMDARs in modulating neural networks and may help us understand neurological diseases such as epilepsy and schizophrenia.
The human brain is an extraordinarily complex machine, with billions of neurons working together in networks to process information and maintain essential functions.
One of the most fascinating features of these neural networks is their dynamic stability: their ability to adapt to changes while maintaining coherent and functional patterns of activity.
Just as our bodies maintain a constant temperature, neurons have homeostatic regulatory mechanisms that ensure that their activity remains within healthy limits. This is crucial because if neurons are too active or too inactive, problems such as seizures or loss of function can arise.
One of the key processes of this regulation is known as firing rate homeostasis (FRH). It acts to adjust the frequency at which neurons fire electrical impulses (or spikes). This adjustment can take minutes, hours, or even days to stabilize activity around a “balance point.”
To understand how this regulation works, scientists are investigating the role of specific molecules in neurons. One of the main targets of this research is N-methyl-D-aspartate receptors (NMDARs).
These receptors act as “gates” that allow calcium to enter neurons, triggering changes that help neurons adapt to new stimuli or learn new information.
NMDARs are particularly interesting because, in addition to being involved in learning and memory, they also appear to play a role in the homeostatic regulation of firing rates. However, previous studies have yielded conflicting results about how these receptors influence this balance.
Researchers at Tel Aviv University have developed a series of innovative experiments to better understand this question.
The scientists used cultures of neuronal networks taken from the hippocampus, a region of the brain that is crucial for memory and learning. In these networks, they monitored the activity of neurons using techniques that allow them to observe electrical firing in real time.
Cultured hippocampal neurons. Image: Stefanie Kaech & Gary Banker. Nature Protocols, volume 1, pages 2406–2415 (2006).
To understand the role of NMDARs, they used chemicals that block these receptors. This allowed them to see what happens when neurons are unable to use these “calcium gates.” They observed how the neurons’ electrical activity changed over time.
The goal was to test whether, even with NMDAR blockade, neurons were able to adjust their firing rates and maintain the overall functioning of the network. They analyzed parameters such as the ratio of excitation to inhibition (a crucial balance to avoid problems such as hyperactivity or paralysis).
To see if the results applied to whole brains and not just cultures, they used mice. In the mice, continuous blockade of NMDARs in the hippocampus was performed while the mice were awake and behaving normally.
The results were surprising and shed light on several previously held doubts. Even with the NMDAR blockade, neural networks were able to adjust their firing rates to a new equilibrium point. This suggests that other compensatory mechanisms kick in when NMDARs are unavailable.
The networks maintained their overall functionality, showing that homeostasis is more robust than previously thought.
While other mechanisms can compensate for their absence, NMDARs play a unique role in modulating the network’s “set point.” That is, they help determine the optimal level of activity for the brain to function efficiently.
Previous studies that found no significant changes after NMDAR blockade likely did not observe changes at the network level, but only in individual neurons.
These findings have important implications for understanding neurological and psychiatric diseases. Disorders such as epilepsy or schizophrenia may be linked to failures in these adjustment mechanisms. Furthermore, the study expands our understanding of how the brain maintains such a delicate balance between plasticity (ability to change) and stability (maintaining functions).
By showing that NMDARs are not only mediators of learning but also fundamental regulators of population activity, scientists have opened new doors for therapeutic interventions in conditions where this balance is disturbed.
READ MORE:
NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics
Antonella Ruggiero, Leore R. Heim, Lee Susman, Dema Hreaky, Ilana Shapira, Maxim Katsenelson, Kobi Rosenblum, and Inna Slutsky
Neuron. November 07, 2024
DOI: 10.1016/j.neuron.2024.10.014
Abstract:
Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) ex vivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs’ capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.
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