DSCAM Mutation Impairs Motor Cortex Network Dynamic and Voluntary Motor Functions.

While it is well known that netrin-1 and its receptors UNC5 and UNC40 family members are involved in the normal establishment of the motor cortex and its corticospinal tract, less is known about its other receptor Down syndrome cell adherence molecule (DSCAM). DSCAM is expressed in the developing motor cortex, regulates axonal outgrowth of cortical neurons, and its mutation impairs the dendritic arborization of cortical neurons, thus suggesting that it might be involved in the normal development and functioning of the motor cortex. In comparison to WT littermates, DSCAM2J mutant mice slipped and misplaced their paw while walking on the rungs of a horizontal ladder, and exhibited more difficulties in stepping over an obstacle while walking at slow speed. Anterograde tracing showed a normal pyramidal decussation and corticospinal projection, but a more dorsal distribution of their axonal terminals in the spinal gray matter. Intracortical microstimulations showed a reduced corticospinal and intracortical efficacy, whereas stimulations of the pyramidal tract revealed a normal spinal efficacy and excitability of corticospinal tract axons, thus arguing for a dysfunctional cortical development. Our study reveals impairment of the network dynamics within the motor cortex, reducing corticospinal drive and impairing voluntary locomotor functions upon DSCAM2J mutation.