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The researchers say that they have defined a possible mechanistic link that explains how a zinc deficiency could contribute to autism. Their study ("Shank and Zinc Mediate a subunit switch of AMPA receptors in developing neurons"), published in Frontiers in Neuroscience Molecular, shows how zinc shapes the synapses between the brain cells that form at the beginning of development, via a complex molecular machinery coded by the risk genes of autism. The findings do not directly support zinc supplementation for autism prevention but broaden our understanding of underlying developmental abnormalities, toward eventual treatment, according to the research team.
"During development, pyramidal neurons undergo dynamic regulation of the AMPA receptor subunit (AMPA) composition and density to promote synaptic plasticity and maturation. These normal developmental changes in AMPAR are particularly vulnerable to risk factors for autism spectrum disorder (ASD), including loss or mutation of synaptic proteins and environmental damage, such as dietary zinc deficiencies. We show here how Shank2 and Shank3 regulate zinc-dependent regulation of the AMPAR function and a missing GluA2 subunit switch to AMPAR containing GluA2. During development, we found a concomitant increase in Shank2 and Shank3 with GluA2 at synapses, implicating these molecules as potential actors in AMPAR maturation, the researchers wrote.
"As the activation and function of Shank require zinc, we then investigated whether neuronal activity regulated postsynaptic zinc at glutamatergic synapses. Zinc has been found to increase transiently and reversibly with neuronal depolarization at synapses, which may affect the localization and activity of Shank and AMPAR. High zinc has induced multiple functional changes in AMPAR, indicative of a subunit switch. Specifically, zinc has lengthened the decay time of AMPAR-mediated synaptic currents and reduced their internal rectification in young hippocampal neurons. Mechanically, Shank2 and Shank3 were required for the enhancement of zinc-mediated AMPAR-mediated synaptic transmission and acted in concert to promote the elimination of GluA1 while enhancing GluA2 recruitment within the preexisting Shank puncta. . These results demonstrate a cooperative local dynamic regulation of the AMPAR subunit switch, controlled by zinc signaling via Shank2 and Shank3, to shape the biophysical properties of synapses under glutamatergic development. Given the zinc sensitivity of young neurons and its dependence on Shank2 and Shank3, genetic mutations and / or environmental damage during early development could alter synaptic maturation and formation of – extend the etiology of ASD. "
"Autism is associated with specific variants of genes involved in the formation, maturation, and stabilization of synapses at the beginning of development," said Sally Kim, lead author of the study, PhD student at the Faculty of Medicine at the University of Ottawa. Stanford University. "Our findings relate zinc levels in neurons via interactions with the proteins encoded by these genes in the development of autism."
Dr. Kim and his colleagues have discovered that when a signal is transferred via a synapse, zinc enters the target neuron where it can bind to two of these proteins: Shank2 and Shank3. These proteins in turn cause changes in the composition and function ("maturation") of adjacent signal receptors, called AMPARs, located on the surface of the neuron at the synapse. Their paper describes the mechanism of zinc-mediated AMPAR maturation in developing synapses.
"In developing rat neurons, we found that Shank 2 and 3 accumulate at synapses in parallel with the passage to mature AMPARs. The addition of extra zinc accelerated the change, but not when we reduced the accumulation of Shank 2 or 3, "said Huong Ha, Ph.D., lead author of the study and a former Stanford graduate student. "In addition, our study mechanically shows how Shank2 and 3 work with zinc to regulate the maturation of AMPAR, a key stage of development."
In other words, zinc determines the properties of developing synapses via Shank proteins.
"This suggests that a lack of zinc early in development could contribute to autism because of an alteration in synaptic maturation and neuronal circuit formation," concluded the lead co-author, John Huguenard, Ph.D., also from the Faculty of Medicine at Stanford University. "Understanding the interaction between zinc and Shank proteins could therefore lead to strategies for diagnosis, treatment and prevention of autism."
"Currently, there are no controlled studies on the risk of autism with zinc supplementation in pregnant women or babies, so the jury is still absent. We can not really draw any conclusions or recommendations regarding zinc supplementation at this time, but experimental work on autism models also published in this report. boundary The research topic is promising, "said Craig Garner, Ph.D., of the German Center for Neurodegenerative Diseases, also a lead co-author.
Taking too much zinc reduces the amount of copper the body can absorb, which can lead to anemia and weakening of the bones. In addition, a deficiency of zinc does not necessarily imply a food deficiency and could result from problems of absorption in the intestine, for example.
"Nevertheless, our findings offer a new mechanism for understanding how zinc deficiency, or disturbed manipulation of zinc in neurons, could contribute to autism," added Dr. Garner.
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