How do we learn to remember? At the most fundamental level, it’s all about chemicals and electricity. Beyond their roles in diet and nutrition, calcium and magnesium work as ions, or charged particles, in the brain. Magnesium can block a channel found within brain receptors known as NMDARs. When the blockade lifts, calcium can pass through the channel. These processes enable the brain to perform essential functions, like learning and remembering.

Scientists have known all of this for a while. What they couldn’t figure out was how NMDARs tell calcium from magnesium. Now, Cold Spring Harbor Laboratory (CSHL) Professor Hiro Furukawa, postdoc Rubin Steigerwald, and colleagues have found an answer that could have implications for brain development and disease. It involves water, dehydration, and a molecular cage captured across 50,000 movies.

If you think back to chemistry class, you might remember that calcium and magnesium sit close together on the periodic table. They also carry the same electrical charge. That makes it hard to tell them apart. One key difference is that “magnesium attracts water more strongly than calcium,” Furukawa says. “It’s more difficult to take out water molecules surrounding magnesium than calcium.”

Since the 1980s, scientists have thought this might explain why calcium passes through the NMDAR channel more easily. It made sense. However, it was impossible to observe. It took decades for imaging technology and computing power to catch up with the theory. But now, using a method called single-particle cryo-EM, Steigerwald and his colleagues have demonstrated how dehydration enables calcium to pass through the NMDAR channel.

Watch as calcium passes through the Asn cage “selectivity filter,” which Hiro Furukawa likens to “a sieve.” This video shows calcium in cyan at five distinct positions from the top to the bottom of the Asn cage, as captured by single-particle cryo-EM.

Steigerwald focused his attention on a part of the channel known as the Asn cage. This molecular cage acts as a filter, allowing only molecules that are small enough to pass. Outside the filter, the team saw magnesium surrounded by water, blocking the channel. If you’re picturing a backed-up spaghetti strainer, you’re right. “It’s a sieve,” Furukawa explains.

So that covers water, dehydration, and the molecular cage. But how do 50,000 movies fit into the picture? “It’s all about resolution,” Furukawa says.

Think about water’s fluid nature. It’s constantly in motion. Tracking the movement of a few water molecules requires high resolution. Single-particle cryo-EM images get you part of the way there. But to really see what’s going on, you need to take millions of images from different angles. Therein lies the power of CSHL’s cryo-EM and high-performance computing cores. Additionally, Furukawa’s team confirmed their observations using electrophysiology.

Why go through all this trouble? Remember, we’re not just talking about chemicals. We’re viewing one of the key molecular features of learning and memory. Furthermore, the Asn cage is susceptible to spontaneous mutations linked to GRIN disorders, which cause severe developmental disabilities. Many patients with these mutations are non-verbal and unable to walk. They often experience severe seizures. To understand the effects of these mutations, you need to know what you’re looking at. This study gives scientists the clearest picture yet.

Written by: Samuel Diamond, Senior Communications Strategist | [email protected] | 516-367-5055