RESUMO
Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro, Adeno-associated virus serotype two overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo, targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy. NT-3 enhanced sprouting and synaptic formation of descending serotonergic, dopaminergic, and propriospinal axons on lumbar MNs, parallel to improved behavioral recovery. Thus, retrogradely transported NT-3 stimulated remodeling of lumbar neural circuitry and synaptic connectivity remote to a thoracic SCI, supporting a role for retrograde transport of NT-3 as a potential therapeutic strategy for SCI.
Assuntos
Atividade Motora/fisiologia , Neurônios Motores/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiopatologia , Animais , Células Cultivadas , Dendritos/fisiologia , Dependovirus/genética , Feminino , Masculino , Camundongos Endogâmicos C57BL , Neurônios Motores/metabolismo , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Vértebras TorácicasRESUMO
Traumatic spinal cord injury (SCI) claims approximately 10,000 new victims each year in the United States alone. The injury usually strikes those under the age of 30 years, often leading to a lifetime of pain, suffering, and disability. Therapeutic agents targeting spinal cord injury are sorely lacking, and therefore our laboratory endeavored to evaluate the potential therapeutic benefits of immediate post-injury administration of the vaccinia virus complement control protein (VCP). VCP is a multifunctional anti-inflammatory protein that can inhibit both pathways of complement activation and bind heparin. Utilizing a common animal model of contusion SCI, motor function recovery tests, and immunochemical stains, we evaluated the effects of VCP injected into spinal cord tissue following injury. Results demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves hind-limb function, establishing VCP as a strong candidate for further investigation in the treatment of SCI.