Semaphorin 7A restricts serotonergic innervation and ensures recovery after spinal cord injury

Abstract

Descending serotonergic (5-HT) projections originating from the raphe nuclei form an important input to the spinal cord that control basic locomotion. The molecular signals that control this projection pattern are currently unknown. Here, we identify Semaphorin7A (Sema7A) as a critical cue that restricts serotonergic innervation in the spinal cord. Sema7A deficient mice show a marked increase in serotonergic fiber density in all layers of the spinal cord while the density of neurons expressing the corresponding 5-HTR2α receptor remains unchanged. These alterations appear to be successfully compensated as no obvious changes in rhythmic locomotion and skilled stepping are observed in adult mice. When the system is challenged with a spinal lesion, serotonergic innervation patterns in both Sema7A-deficient and -competent mice evolve over time with excessive innervation becoming most pronounced in the dorsal horn of Sema7A-deficient mice. These altered serotonergic innervation patterns correlate with diminished functional recovery that predominantly affects rhythmic locomotion. Our findings identify Sema7A as a critical regulator of serotonergic circuit formation in the injured spinal cord.

A deep learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders

“…Importantly, using ALMA, we find profound disturbances in gait and fine paw placement at acute time points following incomplete spinal cord injury and demonstrate a recovery at more chronic time points. This is similar to previous reports that use similar spinal cord injury models 18,20,29,38,46,47 . The application of the ALMA toolbox in such models should both improve the reliability of the analysis (as observer and selection biases are removed) and provide a more refined view of locomotor disturbance and recovery, as it allows the operator to precisely determine which component or components of locomotor function are regulated by a specific circuit modulation or therapeutic intervention.…”

“…This is an important improvement for those investigating skilled paw placement, as it replaces a cumbersome analysis protocol that had to be performed frame by frame 36,37 . The analysis of skilled paw placement is complementary to the obtention of kinematic parameters, as it provides a readout of the damage and recovery of supraspinal circuits 18,38 . Finally, it should be noted that while we focused our analysis on both the gait and footfall aspects of mouse hindlimb movements, the ALMA toolbox should (with minor modifications) be equally suitable for the analysis of forelimb function, forelimb-hindlimb coordination, or the tracking of locomotor function in larger rodents such as rats.…”

Molecular and phenotypic characteristics of 15q24 microdeletion in pediatric patients with developmental disorders

“…The aforementioned SEMA7A gene plays a critical role in neurodevelopment. A recent study identified SEMA7A as a critical cue that restricts serotonergic innervation in the spinal cord [ 23 ]. In PTZ-kindled epileptic rats, Sema7A was upregulated in the epileptic brain and played a potential role in the regulation of seizure activity [ 24 ].…”

A deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders

“…This is an important improvement for those investigating skilled paw placement, as it replaces a cumbersome analysis protocol that had to be performed frame by frame 31,32 . The analysis of skilled paw placement is complementary to the obtention of kinematic parameters, as it provides a readout of the damage and recovery of supraspinal circuits 16,33 . Finally, it should be noted that while we focused our analysis on both the gait and footfall aspects of mouse hindlimb movements, the ALMA toolbox should (with minor modifications) be equally suitable for the analysis of forelimb function, forelimb-hindlimb coordination, or the tracking of locomotor function in larger rodents such as rats.…”

“…Once the mice presented no reflex reaction from paw pinching, their backs were shaved and a laminectomy was performed at T8 levels. The dura was exposed, and a dorsal hemisection was performed using irridectomy scissors 33,49 (Bradley et al, 2019;Loy et al, 2018). After the hemisection, the wound was closed, and the skin was sutured.…”