Abstract: Serotonin is a monoamine neurotransmitter synthetized in various populations of brainstem neurons. In the spinal cord, descending serotonergic projections regulate postural muscle tone, locomotion and rhythm and coordination of movements via the Central Pattern Generator. Following a spinal cord injury, serotonergic projections to the lumbar spinal cord, where the Central Pattern Generators are located, are interrupted resulting in devastating locomotor impairments and changes in the expression and activation of serotonin and its spinal receptors. The molecular cues that control the precise patterning and targeting of serotonergic inputs onto Central Pattern Generator networks in healthy animals or after injury are still unknown. In our recent research work, we have been particularly interested in Semaphorin7A, which belongs to the Semaphorins family involved in guiding growing axons and controlling plasticity of synaptic connections. In this review, we discuss the role of Semaphorin7A signaling as an important molecular actor that instructs the patterning of serotonin inputs to spinal Central Pattern Generator networks. We show that Semaphorin7A controls the wiring of descending serotonin axons in the spinal cord. Our results reveal that mistargetting of serotonin fibers in the spinal cord is compensated in healthy uninjured Semaphorin7A deficient mice so that their gross locomotion proceeds accurately. We also demonstrate that when the system is challenged with a spinal lesion, the pattern of post-injury serotonin expression is significantly altered in Semaphorin7A deficient mice with specific ectopic targeting of serotonin fibers in the lumbar spinal cord. Compensatory mechanisms in place in uninjured Semaphorin7A deficient mice are lost and injured Semaphorin7A deficient mice exhibit a worsening of their post-injury locomotor abilities. Our findings identify Semaphorin7A as a critical determinant of serotonergic circuit formation in healthy or spinal cord injured mice.

Key words: central pattern generator, guidance molecule, locomotion, recovery, rewiring, semaphorin7A, serotonergic patterning, serotonin, spinal cord injury