Houston, Texas, USA : The emergence of autism in children has not only been linked to genes encoding synaptic proteins—among others—but also environmental insults such as zinc deficiency. Although it is unclear whether zinc deficiency contributes to autism, scientists have now defined in detail a possible mechanistic link. Their research shows how zinc shapes the connections or ‘synapses’ between brain cells that form during early development, via a complex molecular machinery encoded by autism risk genes. Published in Frontiers in Molecular Neuroscience, 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.
Zinc and autism risk genes
“Autism is associated with specific variants of genes involved in the formation, maturation and stabilization of synapses during early development,” says study senior author Dr. Sally Kim of 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.”
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.
A mechanistic link
Through an elegant series of experiments, the 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,” explains Dr. Huong Ha – the study’s lead author, 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,” concludes co-senior author Professor John Huguenard, 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.”
Will zinc supplements help prevent 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,” points out Professor Craig Garner 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,” adds Garner.
Citation : Frontiers in Molecular Neuroscience. DOI: 10.3389/fnmol.2018.00405
In a second study Zinc was found to reverse brain cell changes in autism.
Zinc found to reverse brain cell changes in autism
Cellular changes in the brain caused by genetic mutations that occur in autism can be reversed by zinc, according to research at the University of Auckland.
Medical scientists at the University’s Department of Physiology have researched aspects of how autism mutations change brain cell function for the past five years.
This latest work – a joint collaborative effort lead by neuroscientist collaborators in Auckland, America and Germany – was published today in the high impact journal, the Journal of Neuroscience.
The study was funded by the Marsden Fund and the Neurological Foundation.
Lead investigator at the University of Auckland, Associate Professor Johanna Montgomery from the University’s Department of Physiology and Centre for Brain Research, says “This most recent work, builds significantly from our earlier work showing that gene changes in autism decrease brain cell communication.”
“We are seeking ways to reverse these cellular deficits caused by autism-associated changes in brain cells,” she says.”This study looks at how zinc can alter brain cell communication that is altered at the cellular level and we are now taking that forward to look at the function of zinc at the dietary and behaviour level.”
“Autism is associated with genetic changes that result in behavioural changes,” says Dr Montgomery. “It begins within the cells, so what happens at a behavioural level indicates something that has gone wrong at the cellular level in the brain.”
International studies have found that normally there are high levels of zinc in the brain, and brain cells are regulated by zinc, but that zinc deficiency is prevalent in autistic children.
“Research using animal models has shown that when a mother is given a low zinc diet, the offspring will be more likely to display autistic associated behaviours,” she says.
“Our work is showing that even the cells that carry genetic changes associated with autism can respond to zinc.
“Our research has focussed on the protein Shank3, which is localized at synapses in the brain and is associated with neuro-developmental disorders such as autism and schizophrenia,” she says.
“Human patients with genetic changes in Shank3 show profound communication and behavioural deficits. In this study, we show that Shank3 is a key component of a zinc-sensitive signalling system that regulates how brain cells communicate.”
“Intriguingly, autism-associated changes in the Shank3 gene impair brain cell communication,” says Dr Montgomery. “These genetic changes in Shank3 do not alter its ability to respond to zinc”.
“As a result, we have shown that zinc can increase brain cell communication that was previously weakened by autism-associated changes in Shank3”.
“Disruption of how zinc is regulated in the body may not only impair how synapses work in the brain, but may lead to cognitive and behavioural abnormalities seen in patients with psychiatric disorders.”
“Together with our results, the data suggests that environmental/dietary factors such as changes in zinc levels could alter this protein’s signalling system and reduce its ability to regulate the nerve cell function in the brain,” she says.
This has applications to both autism and psychiatric disorders such as schizophrenia.
Dr Montgomery says the next stage of their research is to investigate the impact of dietary zinc supplements to see what impact it has on autistic behaviours.
“Too much zinc can be toxic, so it is important to determine the optimum level for preventing and treating autism and also whether zinc is beneficial for all or a subset of genetic changes that occur in Autism patients.”