Researchers say they have defined a possible mechanistic link that explains how zinc deficiency could contribute to autism. Their study (“Shank and Zinc Mediate an AMPA Receptor Subunit Switch in Developing Neurons”), published in Frontiers in Molecular Neuroscience, shows how zinc shapes the synapses between brain cells that form during early development, via a complex molecular machinery encoded by autism risk genes. The findings do not directly support zinc supplementation for the prevention of autism but extend our understanding of its underlying developmental abnormalities, towards an eventual treatment, according to the research team.

“During development, pyramidal neurons undergo dynamic regulation of AMPA receptor (AMPAR) subunit composition and density to help drive synaptic plasticity and maturation. These normal developmental changes in AMPARs are particularly vulnerable to risk factors for Autism Spectrum Disorders (ASDs), which include loss or mutations of synaptic proteins and environmental insults, such as dietary zinc deficiency. Here, we show how Shank2 and Shank3 mediate a zinc-dependent regulation of AMPAR function and subunit switch from GluA2-lacking to GluA2-containing AMPARs. Over development, we found a concomitant increase in Shank2 and Shank3 with GluA2 at synapses, implicating these molecules as potential players in AMPAR maturation,” wrote the investigators.

“Since Shank activation and function require zinc, we next studied whether neuronal activity regulated postsynaptic zinc at glutamatergic synapses. Zinc was found to increase transiently and reversibly with neuronal depolarization at synapses, which could affect Shank and AMPAR localization and activity. Elevated zinc induced multiple functional changes in AMPAR, indicative of a subunit switch. Specifically, zinc lengthened the decay time of AMPAR-mediated synaptic currents and reduced their inward rectification in young hippocampal neurons. Mechanistically, both Shank2 and Shank3 were necessary for the zinc-sensitive enhancement of AMPAR-mediated synaptic transmission and act in concert to promote removal of GluA1 while enhancing recruitment of GluA2 at pre-existing Shank puncta. These findings highlight a cooperative local dynamic regulation of AMPAR subunit switch controlled by zinc signaling through Shank2 and Shank3 to shape the biophysical properties of developing glutamatergic synapses. Given the zinc sensitivity of young neurons and its dependence on Shank2 and Shank3, genetic mutations and/or environmental insults during early development could impair synaptic maturation and circuit formation that underlie ASD etiology.”

“Autism is associated with specific variants of genes involved in the formation, maturation, and stabilization of synapses during early development,” said study senior author Sally Kim, Ph.D., at the Stanford University School of Medicine. “Our findings link zinc levels in neurons via interactions with the proteins encoded by these genes to the development of autism.”

Dr. Kim and colleagues found that when a signal is transferred via a synapse, zinc enters the target neuron where it can bind two such proteins: Shank2 and Shank3. These proteins in turn cause changes in the composition and function (“maturation”) of adjacent signal receptors, called AMPARs, on the neuron’s surface at the synapse. Their paper describes the mechanism of zinc-Shank-mediated AMPAR maturation in developing synapses.

“In developing rat neurons, we found that Shank 2 and 3 accumulate at synapses in parallel with a switch to mature AMPARs. Adding extra zinc accelerated the switch, but not when we reduced the accumulation of Shank 2 or 3,” explained Huong Ha, Ph.D., the study’s lead author and a former Stanford graduate student. “Furthermore, our study shows mechanistically how Shank2 and 3 work in concert with zinc to regulate AMPAR maturation, a key developmental step.”

In other words, zinc shapes the properties of developing synapses via Shank proteins.

“This suggests that a lack of zinc during early development might contribute to autism through impaired synaptic maturation and neuronal circuit formation,” concluded co-senior author, John Huguenard, Ph.D., also of Stanford University School of Medicine. “Understanding the interaction between zinc and Shank proteins could therefore lead to diagnostic, treatment, and prevention strategies for autism.”

“Currently, there are no controlled studies of autism risk with zinc supplementation in pregnant women or babies, so the jury is still out. We really can’t make any conclusions or recommendations for zinc supplementation at this point, but experimental work in autism models also published in this Frontiers research topic holds promise,” pointed out Craig Garner, Ph.D., of the German Centre for Neurodegenerative Diseases, also co-senior author.

Taking too much zinc reduces the amount of copper the body can absorb, which can lead to anemia and weakening of the bones. Furthermore, zinc deficiency does not necessarily imply a dietary deficiency and could result instead from problems with absorption in the gut, for example.

“Nevertheless, our findings offer a novel mechanism for understanding how zinc deficiency, or disrupted handling of zinc in neurons, might contribute to autism,” added Dr. Garner.

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