Role of DSCAM in the development of the spinal locomotor and sensorimotor circuits.

Locomotion is controlled by spinal circuits that generate rhythm and coordinate left-right and flexor-extensor motoneuronal activities. The outputs of motoneurons and spinal interneuronal circuits are shaped by sensory feedback, relaying peripheral signals that are critical to the locomotor and postural control. Several studies in invertebrates and vertebrates have argued that the Down syndrome cell adhesion molecule (DSCAM) would play an important role in the normal development of neural circuits through cell spacing and targeting, axonal and dendritic branching, and synapse establishment and maintenance. Although there is evidence that DSCAM is important for the normal development of neural circuits, little is known about its functional contribution to spinal motor circuits. We show here that adult DSCAM(2J) mutant mice, lacking DSCAM, exhibit a higher variability in their locomotor pattern and rhythm during treadmill locomotion. Retrograde tracing studies in neonatal isolated spinal cords show an increased number of spinal commissural interneurons, which likely contributes to reducing the left-right alternation and to increasing the flexor/swing duration during neonatal and adult locomotion. Moreover, our results argue that, by reducing the peripheral excitatory drive onto spinal motoneurons, the DSCAM mutation reduces or abolishes spinal reflexes in both neonatal isolated spinal cords and adult mice, thus likely impairing sensorimotor control. Collectively, our functional, electrophysiological, and anatomical studies suggest that the mammalian DSCAM protein is involved in the normal development of spinal locomotor and sensorimotor circuits.