Semaphorin 7A restricts serotonergic innervation and ensures recovery after spinal cord injury
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Semaphorin 7A restricts serotonergic innervation and ensures recovery after spinal cord injury Kristina Loy1,2,3 · Julie Fourneau1,2 · Ning Meng1,2 · Carmen Denecke1,2,3 · Giuseppe Locatelli1,2 · Florence M. Bareyre1,2,4 Received: 26 May 2020 / Revised: 15 September 2020 / Accepted: 9 October 2020 © The Author(s) 2020
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. Keywords Locomotion · Patterning · Recovery · Semaphorin7A · Serotonin · Spinal cord injury
Introduction Serotonin (5-HT) is a monoamine neurotransmitter synthesized by a subclass of neurons termed serotonergic neurons that are present in the brainstem. In higher vertebrates, locomotion is modulated by descending monoaminergic input onto spinal central circuits [1]. Specifically, there are three different aminergic systems that project to Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03682-w) contains supplementary material, which is available to authorized users. * Florence M. Bareyre [email protected]‑muenchen.de 1
Institute of Clinical Neuroimmunology, University Hospital, LMU Munich, 81377 Munich, Germany
2
Faculty of Medicine, Biomedical Center Munich (BMC), LMU Munich, 82152 Planegg‑Martinsried, Germany
3
Graduate School of Systemic Neurosciences, LMU Munich, 82152 Planegg‑Martinsried, Germany
4
Munich Cluster of Systems Neurology (SyNergy), 81377 Munich, Germany
the spinal cord: serotonergic (5-HT), noradrenergic (NA) and dopaminergic (DA). The 5-HT tract system is not only the most widespread one in the mammalian CNS but also the oldest phylogenetically and ontogenetically [2]. The vast majority of 5-HT profiles in the spinal cord originate within the caudal group of the raphe nuclei in particular from the raphe obscurus, raphe pallidus, raphe magnus and vent
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