What causes hyperactivity? The answer may lie not only between your ears, but inside them.
A genetic defect in the inner ear has been shown to cause hyperactive behavior in mice. The mutation ramps up proteins that regulate signaling in the brain, scientists reported Thursday in the journal Science.
These findings may explain why children with severe hearing loss also tend to exhibit hyperactive behavior. Earlier explanations have focused mainly on social and environmental factors, which can be hard to identify. Now, scientists have evidence of “a neurobiological basis for hyperactive behaviors,” said Jean Hébert, a geneticist at the Albert Einstein College of Medicine in New York. “That opens new ways to treat these behaviors.”
Hébert and his colleagues began studying hyperactivity in their mice when they noticed some of them acting strangely: They moved wildly in their cages, running “round and round in little circles” and “jerking their heads chaotically,” Hébert said.
When the researchers later dissected the animals, they noticed that their inner ears were damaged. To investigate whether genetics played a role, the team examined three genes known to be important for inner ear development. One of the genes, called Slc12a2, was missing in the hyperactive mice.
The protein encoded by Slc12a2 produces endolymph, a fluid that bathes the inner ear and is important for maintaining balance. But Slc12a2 is also expressed in the brain, where it controls neuron activity.
Since previous studies had linked hyperactivity to defects in the brain rather than the inner ear, the scientists first determined whether the mice’s restlessness was due to loss of Slc12a2 expression in the brain. They silenced the gene in the brains of several dozen mice and compared them with the same number of normal mice.
The results were puzzling: All the mice whose brains lacked Slc12a2 acted completely normal.
So the researchers repeated the experiment in another batch of mice. But this time, they knocked out Slc12a2 in the inner ear. To their surprise, all the mice were hyperactive.
But how did this ear defect cause hyperactivity? The scientists suspected that it led to increased cell signaling in the striatum, the region of the brain that regulates motor activity.
To test their theory, they screened about 30 brain signaling proteins in the striata of mice whose inner ears lacked Slc12a2. Compared with normal controls, the mutants showed an increase in two proteins -- pERK and pCREB. What’s more, the researchers saw these increases only in the striatum, and nowhere else in the brain.
When the team injected the mutants with a drug that prevented pERK from forming, they behaved normally, further supporting the protein’s role in hyperactivity. The finding also pointed to the pERK pathway as a target for treating hyperactivity in children, especially those with inner ear defects. Up to 77% of kids with inner ear defects show hyperactive behavior, Hébert said.
Even if humans also express Slc12a2, there’s still a chance that a mutation in this gene may not cause the same hyperactivity seen in mice, said Bernd Fritzsch, a geneticist at the University of Iowa who wasn’t involved in the study. “People need to look into the same gene in humans,” he said.
For example, humans may express other genes that have the same function as Slc2a2, so suppressing it won’t have any effect. The remaining normal genes would simply “take over,” he said.
Still, the new study paves the way for future efforts to explore whether hearing and other sensory impairments cause neurological disorders. Scientists have already identified many genes that are expressed in both the ear and the brain, Fritzsch said. The study now gives them “an entire recipe” for testing whether mutations of these genes in the ear can also affect behavior.
Although the new study reveals a neurobiological basis for hyperactivity, socioenvironmental factors may still play a role, Hébert said. “I would guess the combination of socioenvironmental factors and the neurological changes are what together predispose kids to abnormal behaviors,” he said.
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