Scientists have solved a scientific puzzle concerning how the brain distinguishes between two very similar chemical elements, calcium and magnesium, in a process considered fundamental to understanding the mechanisms of learning and memory.
Using advanced imaging technology that captured more than 50,000 video clips, the study revealed why calcium prefers to pass through the brain's channels while magnesium remains stuck outside.
I found that magnesium attracts water molecules more strongly, making it so large that it blocks the neural canal, while calcium loses water, shrinks in size, and passes through it, in a process essential for learning and memory that may also explain serious neurological disorders in children.
It has long been known that learning and remembering are essentially dependent on chemical and electrical interactions within the brain, where calcium and magnesium act as charged molecules.
Magnesium blocks a channel within receptors in the brain known as NMDARs. When this blockage is lifted, calcium can pass through, enabling the brain to perform its essential functions. But the question that has puzzled scientists for decades is: how can these receptors distinguish between calcium and magnesium, two elements that are so similar?
The challenge lies in the fact that calcium and magnesium sit next to each other in the periodic table and carry the same electrical charge, making them very difficult to distinguish. But there is one key difference, explains Professor Hiro Furukawa, the research team leader at Cold Spring Harbor Laboratory: magnesium attracts water molecules much more strongly than calcium, making it more difficult to remove these molecules from around it.
Since the 1980s, scientists have believed that this difference may be the key to explaining why calcium can pass through the canal more easily, but there has been no way to observe and theoretically prove it.
It took decades for imaging technologies and computing capabilities to develop sufficiently to test this theory.
Now, using a cutting-edge technique called single-particle cryo-EM microscopy, researcher Robin Steigerwald and his colleagues have been able to document the entire process. They filmed what happens inside the canal using 50,000 video clips, focusing their attention on a crucial part of it known as the "asparagine cage" (Asn cage), a molecular cage that acts as a fine filter, allowing only sufficiently small molecules to pass through.
What the team saw outside this filter was magnesium surrounded by water molecules, making it too large to pass through, and thus blocking the channel.
Calcium, because it has a weaker affinity for water than magnesium, loses the water molecules surrounding it more easily, becoming smaller and able to pass through the filter without obstruction. This process, which relies on "drying" or the loss of water molecules, explains why calcium preferentially passes through the channel while magnesium remains trapped outside.
To confirm their observations, the team did not rely solely on imaging, but also used electrophysiology to verify the results, because it is not just about chemicals, but about one of the basic molecular mechanisms responsible for learning and memory.
Furthermore, this molecular "cage" that acts as a filter is susceptible to spontaneous mutations associated with disorders known as GRIN, which cause severe and debilitating developmental disabilities. Many patients with these mutations are unable to speak or walk, and often suffer from severe epileptic seizures.
For any hope of understanding the effects of these mutations and developing potential treatments, it was first necessary to see the picture clearly, which this study provides to scientists now for the first time.
