Mouse mannequin reveals root of respiratory points in uncommon type of autism | Spectrum
Exhale: In mice with a mutated copy of the TCF4 gene (right), nerve cells (pink) are in short supply compared to controls (left).
Courtesy Daniel Mulkey
The breathing difficulties in children with Pitt-Hopkins syndrome, a rare form of autism, stem from dysfunctional circuitry and a malignant sodium channel in the brain stem, according to a new mouse study.
About 250 people worldwide have Pitt-Hopkins syndrome, which is characterized by intellectual disability, developmental delay, seizures, and hyperactivity. Up to 50 percent of children with the syndrome also develop breathing problems in which they alternate between breathing quickly and holding their breath.
“This type of breathing can easily contribute to aspiration pneumonia, which is one of the leading causes of death in Pitt-Hopkins,” said lead researcher Daniel Mulkey, professor of physiology and neurobiology at the University of Connecticut at Storrs. It can also interfere with daily activities and cause children to fall or pass out.
The syndrome is caused by mutations in a gene called TCF4, which encodes a protein that helps turn other genes on or off. But the scientists couldn’t explain how this compromised gene translates into specific traits.
The new work, published in Nature Communications in October, attributes the disease’s characteristic breathing problems to a number of neurons in the brain stem and the presence of a sodium channel not normally found in the brain – though there are likely other causes, say the explorers.
“One of the big questions we’ve had all along is, ‘How do we deal with these problems?’ because we don’t know where they’re coming from or what is causing them, ”says Kimberly Goodspeed, an uninvolved assistant professor of pediatrics at the University of Texas Southwestern in Dallas.
The malignant sodium channel, they and others say, could serve as a target for treatment.
Feature film: Mice with a mutation in the TCF4 gene (right) move more in their cages than wild-type mice (left).
Mutated mice:
Mulkey’s team examined mice with a mutated copy of TCF4. Like people with Pitt-Hopkins syndrome, the animals are hyperactive and have impaired breathing, the researchers found. The mice also show less fear-like behaviors than expected in response to certain stimuli.
The team examined neurons in brain slices from the ventral parafacial region, an area of the brain stem that regulates breathing. Neurons that control inhalation couldn’t properly communicate with the rest of the breathing circuit, the researchers found. And 70 percent of a subset of neurons believed to be responsible for exhalation were absent.
The brain slices also contained NaV1.8, a sodium channel normally only found in peripheral nerves. Sodium channels help spread electrical impulses or action potentials through neurons.
Treatment of the TCF4 mutant mice with a sodium channel blocker that can enter the brain alleviated their breathing difficulties, hyperactivity, and anxiety-like behavior. Turning off the sodium channel in neurons that control breathing similarly improved the animals’ breathing. The researchers did not examine any behavioral traits in this experiment.
Researchers aren’t sure how the sodium channels contribute to the symptoms of Pitt-Hopkins syndrome. It may be that “when these cells express this sodium channel, they no longer generate action potentials and therefore cannot maintain their activity,” says Mulkey.
The sodium channel offers a “specific molecular target that could potentially save some of these respiratory problems,” says Eric Levine, a professor of neuroscience at the University of Connecticut who was not involved in the study.
Fresh breath:
The researchers want to investigate how the lack of TCF4 leads to the loss of certain cells in the respiratory system.
“I want to identify genes that are specific for these expiratory cells. Who are they, what are they doing, who are they talking to? ”Says Mulkey.
But it’s also important to look beyond that specific group of neurons to the broader context in which they operate, he says. “They don’t work alone. You live in a neighborhood that contains astrocytes. It includes the regulation of the vascular tone. It comprises inhibitory neurons that all work in a kind of orchestra to control each other and to influence behavior. “
Questions also remain as to whether there are similarities between Pitt-Hopkins syndrome and other autism-related conditions such as Rett syndrome, which involves a similar pattern of breathing disorders. While the cellular and molecular causes of these breathing problems are unlikely to be the same, they can have common side effects.
“Even if the underlying causes of these symptoms are different, they can converge on a similar downstream target as this sodium channel,” says Levine. “That could turn out to be a common factor that could be attacked under these and other conditions.”
Quote this article: https://doi.org/10.53053/LUYL3482
