Abstract
Evidence suggests that motor experience plays a role in shaping development of the corticospinal system and voluntary motor control, which is a key motor function of the system. Here we used a mouse model with conditional forebrain deletion of the gene for EphA4 (Emx1-Cre:EphA4tm2Kldr), which regulates development of the laterality of corticospinal tract (CST). We combined study of Emx1-Cre:EphA4tm2Kldr with unilateral forelimb constraint during development to expand our understanding of experience-dependent CST development from both basic and translational perspectives. This mouse develops dense ipsilateral CST projections, a bilateral motor cortex motor representation, and bilateral motor phenotypes. Together these phenotypes can be used as readouts of corticospinal system organization and function and the changes brought about by experience. The Emx1-Cre:EphA4tm2Kldr mouse shares features with the common developmental disorder cerebral palsy: bilateral voluntary motor impairments and bilateral CST miswiring. Emx1-Cre:EphA4tm2Kldr mice with typical motor experiences during development display the bilateral phenotype of “mirror” reaching, because of a strongly bilateral motor cortex motor representation and a bilateral CST. By contrast, Emx1-Cre:EphA4tm2Kldr mice that experienced unilateral forelimb constraint from P1 to P30 and tested at maturity had a more contralateral motor cortex motor representation in each hemisphere; more lateralized CST projections; and substantially more lateralized/independent reaching movements. Changes in CST organization and function in this model can be explained by reduced synaptic competition of the CST from the side without developmental forelimb motor experiences. Using this model we show that unilateral constraint largely abrogated the effects of the genetic mutation on CST projections and thus demonstrates how robust and persistent experience-dependent development can be for the establishment of corticospinal system connections and voluntary control. Further, our findings inform the mechanisms of and strategies for developing behavioral therapies to treat bilateral movement impairments and CST miswiring in cerebral palsy.
Highlights
Expression of skilled voluntary movements during development depends on the establishment of functional connections between the motor cortex and spinal motor circuits and, in particular, those of the corticospinal tract (CST)
In mature mice subjected to unilateral forelimb constraint, we traced CST projections from the forelimb area of motor cortex (MCX) contralateral to the constrained forelimb and contralateral to the unconstrained forelimb
We showed robust and persistent motor experience-dependent development of the laterality of the CST and the function of the corticospinal system
Summary
Expression of skilled voluntary movements during development depends on the establishment of functional connections between the motor cortex and spinal motor circuits and, in particular, those of the corticospinal tract (CST). Development of this motor pathway reflects an interplay between genetics and neural activity. The activity of the corticospinal system helps steer postnatal development of the topography of spinal connections and the efficacy of the CST in producing motor responses [4, 5]. Related to activity-dependent development, the role of early limb motor experience in CST development is poorly understood. Our knowledge is limited because there have been few studies and the influence of experience on many important aspects of CST organization and function have yet to be examined
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