Pediatric dysphagia (swallowing difficulties) is a frequent and serious clinical complication in a large number of clinically defined neurodevelopmental disorders including the genetic childhood disorder DiGeorge syndrome (also known as 22q11.2 deletion syndrome). Using a mouse model of DiGeorge syndrome, researchers uncovered that the motor neurons that directly control the tongue muscles were firing spontaneously, out of sync with the mechanisms that should control their activity.

Their observations, published in the eNeuro paper, “Disrupted Coordination of Hypoglossal Motor Control in a Mouse Model of Pediatric Dysphagia in DiGeorge/22q11.2 Deletion Syndrome,” provide a foundation for understanding that misfiring neurons—that control key parts of the mouth and tongue—may be creating swallowing difficulties in children with neurodevelopmental disorders.

Problems ingesting, chewing, or swallowing food occur in up to 80% of children with developmental disorders and can lead to food aspiration, choking, or life-threatening respiratory infections. Suckling, feeding, and swallowing difficulties are among the most serious and frequent complications in infants. They are common in DiGeorge syndrome, which is a genetic disease caused when a small part of chromosome 22 is missing. The syndrome carries a high risk for autism spectrum disorder and schizophrenia, as well as heart, face, and limb malformations.

Finding ways to calm the motor neurons responsible for moving the tongue could lead to improved function in very young children who have difficulty swallowing, eating, or making sounds, but the scientists said more research is needed before developing therapies.

In the study, Xin Wang, MD, associate research professor and David Mendelowitz, PhD, vice chair and professor of pharmacology and physiology, both at the George Washington University School of Medicine and Health Sciences, traced the motor neurons in mouse models of DiGeorge syndrome from their target muscles, labeled each class of motor neuron, and recorded their electrical properties.

They write that they “asked whether the physiological and morphological properties of hypoglossal motor neurons (CNXII MNs) that innervate protruder or retractor tongue muscles are disrupted in neonatal LgDel mice that carry a heterozygous deletion parallel to that associated with DiGeorge/22q11.2 deletion syndrome (22q11.2DS).”

The authors noted that heterozygous deletion of the full set of mouse orthologues of human 22q11 genes “disrupts key physiological properties of distinct classes of hypoglossal motor neurons that coordinate oro-pharyngeal function in the LgDel mouse model of 22q11DS, the only established genetic model for pediatric dysphagia.”

The motor neurons responsible for the forward and backward movement of the tongue in the DiGeorge syndrome models spontaneously fired compared with motor neurons of normal mice, and the excitatory impulses were not balanced by inhibitory responses.

More specifically, they found that spontaneous firing, as well as inhibitory post-synaptic current (IPSC) frequency, differed significantly in neonatal LgDel versus WT protruder and retractor CNXII MNs that were identified by retrograde tracing from their target muscles.” They did this work using an in vitro rhythmically active medullary slice preparation.

As a result, the increased excitability of motor neurons affected compression and movement of the tongue muscles, which would threaten both food intake efficiency and airway safety in infants and toddlers.

“We are continuing to make the case that activity of the motor neurons that command the movement of key parts of the mouth, tongue, and pharynx are disrupted by the same mechanisms causing genetic neurodevelopmental disorders,” said Anthony-Samuel LaMantia, PhD, professor, director, center for neurobiology research at the Fralin Biomedical Research Institute at Virginia Tech and co-author of the study. “Our goal is to learn about the causes of these symptoms to help children as early in life as possible.”

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