Bottom line: Acquisition of motor skills during infancy is critical for a child's ability to interact with the physical and social environment and motor impairments are frequent in individuals with neurodevelopmental disorders, including autism. Using a mouse model of a neurodevelopmental disorder and genetic form of autism called DDX3X syndrome, the researchers discovered that the motor deficits depend on a specific brain circuit that connects the cortex with a particular nucleus in the brainstem. The researchers also found that an early intervention can improve motor trajectories, providing insights on the plasticity of the underlying circuits and their potential for therapeutic targeting.
Results: DDX3X syndrome is a genetic form of intellectual disability and autism that primarily affects girls and women. The syndrome is caused by variants in a gene called DDX3X. A genetically engineered mouse model for this condition shows altered morphology and activity of brain cells connecting the cortex with the brainstem. These brain cells are critical for motor performance and the research team found that suppressing the DDX3X gene in only these cells induces motor deficits, specifically in female mice. Additionally, an exercise intervention early in life produced lasting improvements in motor performance that persisted into adulthood.
Why the research is interesting: The findings demonstrate that motor deficits in neurodevelopmental disorders can be associated with defects in specific brain circuits and that these circuits can retain a degree of plasticity later in life. This emphasizes the importance of early-life intervention in neurodevelopmental disorders and identifies potential circuits that can be targeted for treatment.
Who: A mouse model of a rare genetic neurodevelopmental disorder called DDX3X syndrome.
When: Animals were genetically manipulated or exposed to a motor intervention during the juvenile phase.
What: The study examined the function of a brain circuit connecting the cortex with the brainstem and regulating performance during skilled motor tasks.
How: Neurons were labeled using viral particles that express fluorescent molecules and visualized in intact mouse brains after making the tissue optically transparent. The neurons in the cortex projecting to a specific nucleus in the brainstem were genetically manipulated to selectively remove the DDX3X gene. The neurons were also genetically manipulated so that the researchers could either suppress or induce their activation. Motor abilities of the mice were tested using a battery of motor tasks.
Study conclusions: The DDX3X gene is essential for the morphological development and activity of cortical neurons that project to the brainstem to control motor function. The balanced activity of these neurons is essential for proper motor function. Eliminating the expression of the DDX3X gene in the circuit formed by these neurons in juvenile age induces motor deficits. Juvenile mutant mice exposed to the motor intervention had alleviated motor deficits as adults.
Corresponding author: Silvia De Rubeis, PhD, Associate Professor of Psychiatry, Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, and other coauthors.
Paper title: Ddx3x deficiency in mice impairs corticofugal motor circuits and causes motor deficits that are attenuated by early-life exercise
Said Mount Sinai's Dr. Silvia De Rubeis of the research:
"Individuals with neurodevelopmental disorders, including autism, often have motor symptoms, and monitoring motor milestones can facilitate early diagnosis. In the study, we have investigated the biological basis of motor manifestations in DDX3X syndrome, a neurodevelopmental disorder that is a frequent cause of autism in girls and women. We used a genetically engineered mouse model for DDX3X syndrome and discovered a specific brain circuit causing motor deficits in these mice. We also discovered that a motor intervention initiated when the mice are juvenile can significantly improve their motor performance as adults, suggesting that there is still plasticity that can be harnessed for therapeutic intervention. Future studies examining the molecular cascades in these neurons and after early-life motor intervention might reveal new therapeutic targets."
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