Mannequin mice trace at sodium channel gene’s contribution to autism | Spectrum
Channel markers: The cerebral cortex of mice with two mutated copies of SCN2A (bottom) has fewer sodium channels (green) than that of control mice (top).
Some mutations in SCN2A, a gene reliably linked to autism, change the social behavior of mice by dampening the electrical activity of their neurons, according to a new study.
SCN2A encodes a sodium channel that helps neurons send electrical signals. So-called “gain-of-function” mutations make the channel hyperactive and can lead to epilepsy, while “loss-of-function” mutations reduce its activity and are typically associated with autism.
The mice in the new study carry the latter type and therefore have fewer functioning sodium channels than usual. The animals also react in an atypical manner to unfamiliar mice and reflect the social behavior of autistic people with similar SCN2A mutations.
“We are able to really link a single mutation or at least a defect in the channel to the behavior,” says lead researcher Geoffrey Pitt, professor of medicine at Weill Cornell Medicine in New York. “The message our paper shows is that loss of function mutations and decreased sodium current can lead to behavior.”
This study confirms previous work showing that autism-related mutations in SCN2A dampen channel activity in neurons and further links the loss of function mutations to marked behavioral changes, says Kevin Bender, associate professor of neurology at the University of California San Francisco. who was not involved in the work. “The behavioral results were actually some of the most robust I’ve seen in the field.”
Low sodium content:
Pitt and his team used CRISPR to create mice that carried an SCN2A mutation that effectively eliminated some of the sodium channel protein.
This mutation wasn’t seen in humans, Bender says, but it mimics the truncated proteins found in SCN2A in most people with loss of function mutations.
Mice with the mutation in both copies of the gene die shortly after birth and have almost no sodium channel in their cerebral cortex, Pitt’s team found. Therefore, they focused on mice with a mutated copy of SCN2A that have a normal lifespan and less than half the usual amount of the sodium channel.
Pyramidal neurons isolated from the animals’ forebrains were less excitable than those from wild-type mice. Pitt and colleagues also used fiber photometry to monitor the activity of these neurons in the medial prefrontal cortex as the mice moved in a plus-sign-shaped “maze” with two closed arms and two closed arms.
Typical mice tend to spend less time in open arms where they become anxious. They also show a significant increase in neural activity when visiting the open arms. In contrast, the SCN2A mice explored the open arms extensively and showed almost no change in neural activity when moving between the open and closed arms.
“The fact that these cells show no difference in their activity in vivo is remarkable,” says Bender. “It would be really interesting to follow up on that.”
In an animal social behavior test, the SCN2A mice were just as interested in an unknown mouse as wild-type mice, but they stayed that way for much longer. These behaviors roughly agree with clinical data from four autistic people with SCN2A mutations with loss of function who tend to be overly friendly to strangers, the researchers say.
In further analyzes, brain slices from the medial prefrontal cortex and basolateral amygdala of the model mice – areas associated with cognitive and emotional behaviors – showed less frequent spontaneous excitatory postsynaptic currents than brain slices from controls. This finding suggests that the decrease in sodium channels reduced neural firing, which led to impaired neural signal transmission.
“It’s encouraging to see potential similarities between the clinical data and some aspects of our mouse model,” says Pitt. His team’s next step is to study mice with a SCN2A mutation with loss of function found in autistic people, he says.
