A gene mutation strongly linked to severe forms of autism hampers how brain cells communicate and connect with one another, according to new research performed in mice by UC San Francisco scientists.
Unlike other gene mutations linked to autism, which are thought to alter brain development before birth, the newly identified changes in brain signaling may occur closer to the onset of autism symptoms in the first years of life, raising hope that a future therapy could intervene in time to correct the impairment.
“In study after study, researchers keep finding strong associations between this gene and autism,” said Stephan Sanders, BMBS, PhD, an assistant professor of psychiatry at UCSF, who was a member of the Yale team – led by Matthew State, MD, PhD, now Oberndorf Family Distinguished Professor and chair of psychiatry at UCSF – that first identified the gene, called SCN2A, as a gene implicated in autism in 2012.
“This is one of the top two out of over a hundred genes now associated with autism, and the connection just gets stronger and stronger,” Sanders said.
The SCN2A gene produces a key type of sodium channels in cells, which are essential for neurons to produce the electrical signals they use to communicate with one another. How impeding the channels’ function might lead to autism, though, has been unclear.
In the new study, published June 20, 2019, in Neuron, researchers deleted one copy of the SCN2A gene in mice, resulting in half the normal number of viable sodium channels. This led to two problems: During early brain development, it made neurons less “excitable,” reducing the number of signals they fired; later on, though the cells’ firing rates returned to normal, while the strength of synapses – the connections between neurons – which depends on those electrical communications, got weaker.
“We’ve condensed a complex, multi-faceted disorder into two cellular changes, which makes the problem much more tractable,” said Kevin Bender, PhD, an assistant professor of neurology at UCSF and senior author on the paper. “Combined with our earlier research with Stephan that first laid out how autism-associated mutations in SCN2A alter sodium channel function, we now have a good idea of the cell type, brain region, and the change in functions that result in autism when SCN2A is affected.”
Kevin Bender, PhD
Neuroscientists have previously shown that the sodium channels in question initially exist primarily in the part of a neuron called the axon, a long, thin, wire-like extension that relays electrical signals to the next cell in a chain. As expected, neurons with fewer sodium channels in their axons are less able to fire, explaining their reduced excitability.
But partway through brain development, neurons change how and where they use these channels. After the first week of life in mice (roughly equivalent to a year in a human), the channels are replaced by a different type of sodium channel in the axon, and instead began to show up in a different set of structures, called dendrites, which receive signals from other cells. There, the SCN2A channels appear to help strengthen synaptic connections between cells. Experiments reported in the new study showed that as a result, cells with fewer of these sodium channels ended up with weaker synapses overall.
A major clinical concern in the field is that if the brain changes that lead to autism occur during the first year of life or earlier, such as during in utero brain development, it would be very difficult to identify the problem early enough to intervene. But if autism is driven by problems with later phases of brain development, as the new study suggests could be the case, scientists may find ways to correct the problem in time.
“The big question now is, which of these two effects lead to autism? Is it a decrease in excitability, a decrease in synaptic strength, or is it both?” said Bender. “From a therapeutic point of view, this is critical because if it’s the decrease in excitability, we’ve probably missed the boat. But if it’s the synapse, we could potentially fix the problem because the changes don’t emerge until later.”
The scientists are now exploring genetic interventions to correct the SCN2A mutation in mice, which could one day lead to gene therapy capable of treating the disorder in humans with similar sodium channel impairments.
“We went into this study thinking that the earliest stage of development was going to be the most important, which would make treatment much harder, if not impossible,” Sanders said. “This finding gives us hope, because even in kids who are diagnosed relatively late, there’s still the potential for a therapeutic.”