Gene linked to autism and epilepsy directs speed of human brain cell development

First study in human cells illuminates functions of SYNGAP1 autism gene.

October 20, 2020

JUPITER, FL—A gene whose dysfunction is linked to autism and other brain-development disorders has a critical role in the growth of healthy neurons, directing the speed at which the neurons mature, according to a new study.

The study, published this month in the Journal of Neuroscience by Scripps Research neuroscientist Gavin Rumbaugh, PhD, investigates the role of the gene SYNGAP1 in the early development of human neurons.

Changes to SYNGAP1 that inactivate the gene cause a rare autism disorder called MRD5, which also typically features intellectual disability and epilepsy. When these mutations occur spontaneously in the womb and alter one of the two copies of the gene, they cause neurodevelopmental problems.

“The SYNGAP1 gene appears to be necessary for healthy human brain development, and here we’ve found that its role, at least in part, is to set the correct pace for neurons’ maturation,” Rumbaugh says.

Only a few hundred cases of MRD5 disorder have been diagnosed, but large-scale gene studies suggest that the prevalence is likely much higher. Neuroscientists expect that by studying how rare SYNGAP1 mutations cause developmental abnormalities, they will better understand the pathways through which autism arises generally.

In the new study, Rumbaugh and his team took healthy human stem cells, induced them to turn into developing neurons, and observed their development when SYNGAP1 was excised or left intact. They found that removing SYNGAP1 caused the developing neurons to essentially mature differently.

In those lacking two functional copies of SYNGAP1, the rootlike tendrils, called dendrites, through which neurons receive input signals from other neurons, started growing earlier and became bushier, compared to the dendrites in normal neurons. Also, their connection points, or synapses, developed earlier and became stronger and more numerous.

The findings are consistent with Rumbaugh’s prior studies of SYNGAP1 loss in mouse neurons, and also appear to reflect major features of MRD5 disorder. Inherently overactive brain circuits can be a cause of epilepsy, for example. In principle, they can lead to the kinds of imbalances in circuit activity that have been linked to repetitive behaviors in autism, Rumbaugh says. Also, children with MRD5 and other autism-related disorders are sometimes easily overwhelmed by noises and other sensory signals, hinting at excessive signal strength in some sensory circuits, he adds.

“We suspect one of the reasons humans have problems when they lose function of SYNGAP1 is that their neurons mature too quickly in certain areas of the brain,” Rumbaugh says. “They wire up and cause activity too quickly, and disrupt the usual balance between excitatory and inhibitory circuits so that the brain can’t control itself properly.”

Rumbaugh communicates with many families of MRD5 patients. His next step is to continue the studies using neurons derived from these patients. His lab also will collaborate with other labs that study such neurons in three-dimensional clumps called organoids, which can reveal a wider range of features of neuronal development.

“Kids with MRD5 have loss-of-function mutations in only one copy of SYNGAP1, so our hope ultimately is to find a treatment that increases expression of the remaining good copy, restoring the net production of the SynGAP protein to normal,” Rumbaugh says. “Potentially that would be a cure if delivered early enough.”

“SYNGAP1 Controls the Maturation of Dendrites, Synaptic Function, and Network Activity in Developing Human Neurons” was authored by Nerea Llamosas, Vineet Arora, Camilo Rojas, Adrian Reich, BanuPriya Sridharan, Louis Scampavia, Timothy Spicer, Courtney Miller, and Gavin Rumbaugh, all of Scripps Research; and by Ridhima Vij and Lloyd Holder, Jr. of Texas Children’s Hospital, Lukasz Bijoch of the Polish Academy of Sciences, and Erik Willems and David Piper of Thermo Fisher Scientific.

The research was supported by the U.S. National Institute of Mental Health (MH096847, MH108408), the National Institute for Neurological Disorders and Stroke (NS064079, NS110307, NS091381), the SynGAP Research Fund, the Doris Duke Charitable Foundation, and Leon and Friends e.V.

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