Context-Dependent Gait Choice Elicited by EphA4 Mutation in Lbx1 Spinal Interneurons

•Limb load and age influence gait choice in Lbx1 EphA4 conditional mice•Lbx1 EphA4 conditional mice alternate on ground but switch to synchrony in water•Dorsal premotor interneurons connect bilaterally in Lbx1 EphA4 conditional mice•Ectopic premotor interneurons receive sensory input in Lbx1 EphA4 conditional mice

SummaryThe most commonly used locomotor strategy in rodents is left-right limb alternation. Mutation of the axon guidance molecule EphA4 profoundly alters this basic locomotor pattern to synchrony. Here we report that conditional mutation of EphA4 in spinal interneurons expressing the transcription factor Lbx1 degrades the robustness in the expression of left-right alternating gait during development. Lbx1 EphA4 conditional mice exhibit alternating gait when walking on ground, but synchronous gait in environments with decreased weight-load, like swimming and airstepping. Using cell-type-specific, transient pharmacogenetic silencing approaches, we attribute this behavioral gait switch to neuronal activity of dorsal Lbx1 spinal interneurons. We also found that in Lbx1 EphA4 conditional mice these dorsal interneurons form aberrant bilateral connections to motor neurons, thereby indirectly transmitting received unilateral proprioceptive sensory information to both spinal sides. Together, our findings reveal the behavioral and circuit-level impact of conditional EphA4 mutation in a transcriptionally defined spinal interneuron subpopulation.