HMN 2026: How NMDA receptor maps may explain memory-linked calcium flow

The human brain constantly adapts in response to experiences, forming new connections between neurons and reorganizing existing ones. The brain’s ability to adapt in response to experiences is known as neuroplasticity.

One form of neuroplasticity, called Hebbian plasticity, entails the strengthening of communication between neurons that become repeatedly active at the same time. This strengthening of connections between neurons that fire together has also been found to be linked to so-called N-methyl-D-aspartate (NMDA) receptors, specialized protein channels located in neuronal membranes.

NMDA receptors are activated by the neurotransmitter glutamate and the signaling molecule glycine. They also respond to a temporary reduction in electrical charge differences across cell membranes, known as membrane depolarization.

When NMDA receptors are activated, they allow positively charged calcium ions (Ca²⁺) to enter neurons, which can contribute to the strengthening of synapses (i.e., junctions connecting neurons). The same receptors, however, can also be blocked by magnesium ions (Mg²⁺), which prevent the flow of ions under resting conditions.

Researchers at Cold Spring Harbor Laboratory carried out a study aimed at better understanding how NMDA receptors differentiate between Ca²⁺ and Mg²⁺ cations.

Their paper, published in Nature Neuroscience, offers evidence of a molecular mechanism that allows NMDA receptors to selectively allow Ca²⁺ to enter cells, while being blocked by Mg²⁺ ions at rest, contributing to the Hebbian neuroplasticity that supports memory and learning.

“Mg²⁺ and Ca²⁺ are present in the biological system, and are used differently by ion channels,” Hiro Furukawa, senior author of the paper, told Medical Xpress.

“In the case of NMDA receptors, Ca²⁺ influx into cells facilitates signaling that leads to neuroplasticity and, in some cases, neurodegeneration. Mg²⁺, on the other hand, is an effective blocker of NMDA receptor channels at the resting membrane voltage, but the blockade gets relieved by membrane depolarization.”

Visualizing NMDA receptors at high resolution

Mg²⁺ and Ca²⁺ have similar chemical properties, yet NMDA receptors respond differently to these two cations. The objective of the team’s study was to better understand the molecular processors via which the receptors tell the two ions apart.

“Mg²⁺ block and Ca²⁺ permeation are functional features that establish NMDA receptors as prominent molecules involved in learning and memory,” said Furukawa. “We wanted to understand how these ions exert their effects on NMDA receptor ion channels at the molecular level by visualizing them.”

As part of their study, Furukawa and his colleagues studied NMDA receptors in vitro (i.e., outside of the body, under the microscope), using a technique known as single-particle cryo-electron microscopy. This technique allowed them to visualize the receptors with a very high resolution.

The researchers also collected electrical measurements to explore how Mg²⁺ ions block the receptor. Their analyses also allowed them to pinpoint calcium-binding sites inside the receptor’s selectivity filter (i.e., the region controlling the passage of ions).

“We used a combination of single-particle cryo-electron microscopy (cryo-EM) to obtain high-resolution structures of NMDAR bound to Ca²⁺ or Mg²⁺ and electrophysiology to measure channel activity to further assess Mg²⁺ block,” explained Furukawa.

“The quality of the data was sufficient to reveal the hydration patterns of Mg²⁺ and Ca²⁺ in the channel pore. In other words, we found that Mg²⁺ and Ca²⁺ bind to H₂O molecules in a specific manner. How they hydrate and dehydrate is essential for understanding why Mg²⁺ blocks the channel while Ca²⁺ can pass through.”

Exploring the chemistry of memory and learning

The team’s experiments allowed them to identify a molecular mechanism via which NMDA receptors could distinguish between Mg²⁺ and Ca²⁺ ions. Specifically, they found that Ca²⁺ partly shed water molecules and this allows them to squeeze through the receptor’s narrow channel. In contrast, Mg²⁺ remains hydrated and does not enter the channel, blocking it from outside the selectivity filter.

This study offers new insight into how NMDA receptors support Hebbian neuroplasticity. If they are validated in further research, they could help to delineate the molecular chemistry processes that support memory and learning.

This could also potentially inform the development of new NMDA-targeting treatments for neurological or psychiatric disorders associated with a decline in mental functions and memory loss, such as neurodegenerative diseases and schizophrenia.

“As part of our next studies, we would love to monitor Mg²⁺ binding at controlled membrane voltages since the binding strength is voltage-dependent,” added Furukawa.

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