Mechanisms involved in spinal cord central synapse loss in a mouse model of spinal muscular atrophy.

Motoneuron (MN) cell death is the histopathologic hallmark of spinal muscular atrophy (SMA), although MN loss seems to be a late event. Conversely, disruption of afferent synapses on MNs has been shown to occur early in SMA. Using a mouse model of severe SMA (SMNΔ7), we examined the mechanisms involved in impairment of central synapses. We found that MNs underwent progressive degeneration in the course of SMA, with MN loss still occurring at late stages. Loss of afferent inputs to SMA MNs was detected at embryonic stages, long before MN death. Reactive microgliosis and astrogliosis were present in the spinal cord of diseased animals after the onset of MN loss. Ultrastructural observations indicate that dendrites and microglia phagocytose adjacent degenerating presynaptic terminals. Neuronal nitric oxide synthase was upregulated in SMNΔ7 MNs, and there was an increase in phosphorylated myosin light chain expression in synaptic afferents on MNs; these observations implicate nitric oxide in MN deafferentation and suggest that the RhoA/ROCK pathway is activated. Together, our observations suggest that the earliest change occurring in SMNΔ7 mice is the loss of excitatory glutamatergic synaptic inputs to MNs; reduced excitability may enhance their vulnerability to degeneration and death.

Neuregulin-1 is concentrated in the postsynaptic subsurface cistern of C-bouton inputs to α-motoneurons and altered during motoneuron diseases.

C boutons are large, cholinergic, synaptic terminals that arise from local interneurons and specifically contact spinal α-motoneurons (MNs). C boutons characteristically display a postsynaptic specialization consisting of an endoplasmic reticulum-related subsurface cistern (SSC) of unknown function. In the present work, by using confocal microscopy and ultrastructural immunolabeling, we demonstrate that neuregulin-1 (NRG1) accumulates in the SSC of mouse spinal MNs. We also show that the NRG1 receptors erbB2 and erbB4 are presynaptically localized within C boutons, suggesting that NRG1-based retrograde signaling may occur in this type of synapse. In most of the cranial nuclei, MNs display the same pattern of NRG1 distribution as that observed in spinal cord MNs. Conversely, MNs in oculomotor nuclei, which are spared in amyotrophic lateral sclerosis (ALS), lack both C boutons and SSC-associated NRG1. NRG1 in spinal MNs is developmentally regulated and depends on the maintenance of nerve-muscle interactions, as we show after nerve transection experiments. Changes in NRG1 in C boutons were also investigated in mouse models of MN diseases: i.e., spinal muscular atrophy (SMNΔ7) and ALS (SOD1(G93A)). In both models, a transient increase in NRG1 in C boutons occurs during disease progression. These data increase our understanding of the role of C boutons in MN physiology and pathology.

El diálogo bioético en las técnicas de reproducción asistida / Bioethics dialogue in assisted reproductive techniques

En las Técnicas de Reproducción Asistida (TRA) se enfrentan dos agentes morales en diálogo informado: el equipo médico y la pareja con problemas de infertilidad o esterilidad. Se entiende que el hijo es un bien humano básico para ambas partes. Existe el peligro del cientificismo y del peso excesivo de la comercialización de estas técnicas. Además, es necesario establecer correctamente las condiciones para que ese diálogo médico-paciente respete las normas éticas racionales del discurso desde la perspectiva de la ética dialógica, y tener en cuenta los intereses y derechos del hijo en cuanto el otro presente-ausente. El personalismo y la ética de los bienes básicos pueden complementar el análisis de los dilemas éticos que conllevan las TRA.

In assisted reproductive techniques two moral agents are confronted in informed dialogue: the medical team and the couple with infertility or sterility problems. The offspring in this dialogue is a basic human rights for both parts. There is danger of scientificism and of giving excessive importance to the commercialization of these techniques. Furthermore, it is necessary to establish the conditions to respect the rational ethical norms of discourse in the physician-patient dialogue, under the dialogical ethical perspective and to consider the interests and rights of the offspring as the other present-absent. The personalized bioethics perspective and the ethics of basic goods may complement the ethical dilemma's analysis related to assisted reproductive techniques.

Nas Técnicas de Reprodução Assistida (TRA) nos encontramos com dois agentes morais que se enfrentam no diálogo informado: a equipe médica e o casal com os problemas de infertilidade ou esterilidade. Entende-se que nesse dialogo o filho é um bem humano básico para ambas as partes. Existe o perigo do cientificismo e do peso excessivo da comercialização destas técnicas. Além disso, é necessário estabelecer corretamente as condições para esse diálogo médico-paciente respeito das normas éticas racionais do discurso, desde a perspectiva da ética dialógica e levar em conta os interesses e direitos do filho enquanto o outro presente-ausente. O personalismo e a ética dos bens básicos podem complementar a análise dos dilemas éticos envolvidos nas TRA.