How mutations in prime autism gene may result in seizures | Spectrum
Some mutations that disable SCN2A, one of the genes most closely linked to autism, can make neurons unexpectedly hyperexcitable, a study in mice shows. The results could help explain why a significant proportion of autistic children with mutations in SCN2A have epileptic seizures.
SCN2A codes for Nav1.2, a sodium ion channel that helps transmit electrical impulses through neurons in the brain. Mutations that increase the activity of the canal have been linked to seizures in infancy, previous research shows, while mutations that involve “loss of function” – those that interfere with the activity of the canal – have been linked to intellectual disability and autism.
But about a quarter of people with functionless mutations in a single copy of SCN2A also develop epilepsy, which puzzles researchers: seizures typically result from an abundance of excitatory signals; Mutations that block or reduce the activity of the sodium channel would likely silence these signals.
“You have dampened the excitatory drive of the neural network, so why should neurons become more excitable? It just didn’t make sense, ”says lead researcher Kevin Bender, associate professor of neurology at the University of California at San Francisco.
The new study reveals the cellular mechanisms that could explain this seeming paradox, says Bender.
Channel activity:
Bender and his colleagues previously showed that in mice that only have one functional copy of SCN2A, excitatory cells, so-called pyramidal neurons, cannot be overexcited. Instead of having seizures, the rodents have slower than average brain signals and immature synapses.
This time, the team analyzed mice that were missing both copies of SCN2A in pyramidal cells of the prefrontal cortex, a region of the brain involved in social behavior and other activities related to autism. The neurons were overexcitable and often fired action potentials – the researchers found the electrical spikes that transmit signals along neural projections.
Further experiments showed that, in the absence of SCN2A, the cell’s action potentials are not large enough to activate voltage-gated potassium ion channels. These channels usually open after a neuron fires, allowing potassium ions to flow out of the cell, which helps turn the neuron off. However, the loss of SCN2A prevents the cells from reverting to an “off” state, making them overexcitable and increasing the risk of seizures, says Bender.
The loss of more than 50 percent of the Nav1.2 activity increases the excitability of the neurons dramatically, as additional computer simulations suggest. This threshold could explain why only some children with mutations in one copy of SCN2A are susceptible to seizures.
“These kids live on a cliff of susceptibility to seizures, and if they have something in their genome or in their environment that makes them more likely to have seizures, then they could have seizures,” says Bender. The results were published in Cell Reports this week.
Restoring the balance:
The new study provides compelling evidence of the link between SCN2A loss and epilepsy, says Jun Hee Kim, associate professor of cellular and integrative physiology at the University of Texas Health Science Center at San Antonio. The interaction between sodium and potassium channels “makes a lot of sense,” she says.
In another study on mice, published this week in the same journal, the researchers found that a significant decrease in SCN2A protein levels triggers a compensatory downregulation of potassium channels. This shift leads to overexcitable neurons in the cortex and striatum that control movement and other behaviors and have been linked to autism.
The results show why ion channels shouldn’t be studied in isolation, says Anastasios Tzingounis, a professor of physiology and neurobiology at the University of Connecticut who wasn’t involved in the new study. Instead, researchers should study how mutations in one channel affect the activity of others.
The development of humans takes much longer than that of the mouse, warns Tzingounis. In future studies, researchers should keep this in mind when trying to explain how loss of SCN2A could lead to epilepsy in people, he says.
But the new study suggests a mechanism that can be tested, says Tzingounis. “Most studies don’t.”
The results also suggest a testable treatment, says Bruce Bean, a professor of neurobiology at Harvard Medical School, who was not involved in the work. Treating children lacking a copy of SCN2A with standard sodium channel inhibitors would be counterproductive, he says, but modulating the activity of certain potassium channels could help control their seizures.
What makes some children with SCN2A mutations more prone to seizures remains unclear, says Bean, but comparing genomic analyzes of people who develop epilepsy with those of people who don’t could be instructive.
Quote this article: https://doi.org/10.53053/TENO6849
