Worms stuck in repeat could clarify human diseases

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Scientists have identified a brain circuit that underlies repetition in roundworms—a finding that could one day shed light on similar behavior in humans.

Repetition can be useful if you’re trying to memorize a poem, master a guitar riff, or just cultivate good habits. But when this kind of behavior becomes compulsive, it can get in the way of normal life—an impediment sometimes observed in psychiatric illnesses like Tourette’s syndrome and autism spectrum disorders.

When researchers looked at the microscopic roundworm C. elegans, they found that defects in one protein cause them to reorient themselves over and over again.

The new observations, which previous research with mice support, suggest that similar mechanisms may drive repetitive behavior in a range of animals, including humans.

Brain disruption

Scientists initially set out to understand how astrocytes, star-shaped cells found in mammalian brains, help neurons do their job. Researchers think that astrocytes are responsible for, among other things, disposing of excess neurochemicals at synapses, the connections between neurons. This task is vital because if not removed in a timely fashion, these chemicals can stimulate neurons in unexpected ways, disrupting normal brain function.

To better understand the process, Menachem Katz, a research associate in the lab of Rockefeller University professor Shai Shaham, looked to C. elegans CEPsh glial cells, which he suspected were the worm equivalents of astrocytes.

Confirming this suspicion, the researchers used mRNA sequencing to show that mouse astrocytes and CEPsh glia have similar genetic signatures. Among other commonalities, both cell types produce the protein GLT-1, the mammalian version of which is responsible for clearing the chemical glutamate away from synapses. This finding gave the researchers a unique opportunity to define how astrocytes and GLT-1 work, Shaham says.

“Scientists have been trying to understand the functions of astrocytes for many years, and in mammals it’s not easy because these cells are essential for keeping neurons alive. But in C. elegans there are only four CEPsh glial cells, and neurons don’t need them to survive. This allowed us to investigate the specific roles of glutamate transporters, without worrying about the side effects of neuron sickness.”

Back, forward, repeat

To do so, the researchers created C. elegans lacking GLT-1. Surprisingly, the depletion didn’t result in glutamate accumulation at synapses, as the researchers expected. Instead, the worms exhibited oscillations in synaptic glutamate levels—and a peculiar behavioral defect.

“These animals changed their direction at a crazy rate. They just kept moving forward and going back, moving forward and going back,” Shaham says. “And when we analyzed this behavior, we discovered that they did so in a really interesting pattern.”

It’s perfectly normal for C. elegans to change course every now and then. Typically, the worm reorients itself about once every 90 seconds. But worms lacking GLT-1 took this action to the extreme: at 90 second intervals the animals executed not one reversal, but bursts of them. “It’s as if once they start the action, they can’t stop repeating it,” Katz says.

Further experiments revealed that removal of the glutamate receptor MGL-2 blocked both repetitive reversals and synaptic glutamate oscillations. The researchers concluded that when glutamate isn’t efficiently cleared, the chemical stimulates MGL-2, which in turn triggers the release of yet more glutamate. This process then repeats on a loop; and with every release of glutamate, it activates the neuron responsible for initiating reversals.

“These findings suggest a simple model for how repetition can occur in worms,” says Katz. “And, it turns out, this model may hold up in more complex nervous systems.”

Indeed, past experiments have shown that GLT-1 mutations cause repetitive grooming in mice, and that compounds blocking the mouse version of MGL-2 eliminate similar behavior in other contexts.

Taken together with the new findings in C. elegans, the findings suggest that abnormal glutamate secretion may underlie repetitive behaviors across the animal kingdom—raising the possibility that they may be relevant to understanding pathological repetition in humans.

Consistent with this idea, human genetics studies have found mutations associated with glutamate signaling in patients with obsessive compulsive disorder and autism spectrum disorders, both of which can be accompanied by repetitive behavior.

“We were really excited to see these links in the scientific literature because it means our findings may help uncover a plausible mechanism underlying an important class of human diseases,” says Shaham. “And, more broadly, we’re showing that candidate genes affected in human disease can be studied and verified in the simpler worm.”

The study appears in Nature Communications.

Source: Rockefeller University