Ddx3x deficiency in mice impairs corticofugal motor circuits and causes motor deficits that are attenuated by early-life exercise

The X-linked RNA helicase DDX3X is a high-risk gene for autism spectrum disorder and intellectual disability primarily in females. Individuals with pathogenic variants in DDX3X have pervasive and often severe motor manifestations. Using mouse models, we studied the circuits underlying the motor phenotypes associated with Ddx3x deficiency and examined the feasibility of an early intervention to ameliorate motor trajectories. We show that Ddx3x controls both the development and later plasticity of motor circuits connecting the motor cortex with the pontine nuclei. Ddx3x haploinsufficiency during development affects the dendritic arborization of corticopontine neurons. Juvenile-onset Ddx3x loss in corticopontine neurons is sufficient to induce adult motor impairments overlapping with those caused by chemogenetic disruption of corticopontine circuits. Further, Ddx3x mutant mice engage corticopontine circuits in skilled motor tasks in a sex-dependent manner. Last, Ddx3x haploinsufficient female mice undergoing a juvenile motor intervention show long-lasting specific benefits in their adult motor function. Together, these findings establish Ddx3x as an essential regulator of corticopontine neuron development and function and provide an early motor intervention to ameliorate motor outcomes in a mouse model of DDX3X haploinsufficiency.