In biology, structure equals function. The protein machines that do virtually all of the myriad biochemical jobs within every living cell sometimes require the presence of a molecule or two of an elemental substance — copper, iron, manganese, chromium, or what have you — so they can assume just the right shape and wheel into action.
You can read any multivitamin label to view the panoply of nutritionally required trace elements. One of them is zinc, whose role in nervous system function is being busily hammered out by brain scientists — and not without a note of urgency. Several epidemiological studies in recent years have found that low zinc levels, as measured in hair samples, among children with autism spectrum disorder. The association is far from air-tight — plenty of kids with ASD have normal zinc levels — but it hints at a link between zinc and the way we think.
Studies at the molecular level have suggested that zinc plays an important role in the forging of synapses, the customized, complicated contact junctions via which nerves relay impulses to one another. But while these studies have identified scattered pieces of a complex puzzle, they haven’t assembled those pieces into a plausible picture of where and how, exactly, zinc fits into the picture. Now, a study in Frontiers in Molecular Neuroscience puts the pieces together, presenting a working model that could point to a better understanding of autism’s underpinnings.
The new study, led by Stanford neuroscientists John Huguenard, PhD, and Sally Kim, PhD, and then-graduate student Huong Ha, PhD, showed that zinc is required for the proper behavior of two related proteins, Shank 2 and Shank 3, that hang out at most synapses in the brain. Among their duties, Shank 2 and Shank 3 can reshuffle the subunits of a receptor that dots the receiving end of most nerve cells. This receptor gets tripped off by an incoming chemical signal called glutamate.
In the developing brain, glutamate receptors undergo a process of maturation in the form of internal alterations that are catalyzed by Shank 2 and Shank 3. The substitution of one type of subunit for another type in these receptors endow the receptor with more-prolonged signaling strength, a better “memory” of how often it’s been previously tripped off by the arrival of a glutamate molecule, and a correspondingly more-pronounced propensity to respond heartily to such chemical messages in the futaure. (This collection of characteristics, which neuroscientists call “plasticity,” is the molecular essence of memory and learning.)
Kim, Huguenard, Ha and their colleagues showed that zinc is absolutely necessary to this development-associated maturation of glutamate receptors by Shank 2 and Shank 3. When triggered by glutamate, a receiving nerve cell opens itself to a temporary but substantial influx of zinc, molecules of which bind to Shank 2 and Shank 3. This, in turn, spurs those two proteins’ active reshuffling of the cell’s glutamate-receptor molecules — an essential and permanent step in the brain circuitry’s development.
Glutamate-receptor maturation is particularly critical in late fetal and early-childhood brain development, when synapses are being formed at an amazing rate. And zinc deficiency is especially pronounced in the very youngest patients diagnosed with ASD. So it’s only natural to ask whether zinc supplementation can stave off the syndrome.
But that’s by no means been demonstrated, in this study or anywhere else. Moreover, excess zinc intake can be outright dangerous. So tread lightly here. But we’re a step closer to understanding the early wiring up and firing up of the brain’s circuitry — and what can go wrong with it.
Photo by psyberartist