期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 77, 期 7, 页码 577-597出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nly033
关键词
C-boutons; Microglia; Motoneuron synaptic afferents; Sigma-1 receptor; Smn2B/- mouse; SMN Delta 7 mouse; Spinal muscular atrophy
资金
- Ministerio de Economia y Competitividad
- FEDER [SAF2015-70801]
Spinal muscular atrophy (SMA) is characterized by the loss of alpha-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn(2B/-) mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn(2B/-) mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn(2B/-) animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2(B/-) mice. These effects were also observed in a severe SMA model, the SMND7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice.
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