Abstract
The Wobbler mouse is an accepted model of sporadic amyotrophic lateral sclerosis. The spinal cord of clinically symptomatic animals (3–5 months old) shows vacuolar motoneuron degeneration, inflammation, and gliosis accompanied by motor impairment. However, data are not conclusive concerning pathological changes appearing early after birth. To answer this question, we used postnatal day (PND) 6 genotyped Wobbler pups to determine abnormalities of glia and neurons at this early age period in the spinal cord. We found astrogliosis, microgliosis with morphophenotypic changes pointing to active ameboid microglia, enhanced expression of the proinflammatory markers TLR4, NFkB, TNF, and inducible nitric oxide synthase. The astrocytic enzyme glutamine synthase and the glutamate-aspartate transporter GLAST were also reduced in PND 6 Wobbler pups, suggesting excitotoxicity due to impaired glutamate homeostasis. At the neuronal level, PND 6 Wobblers showed swollen soma, increased choline acetyltransferase immunofluorescence staining, and low expression of the neuronal nuclear antigen NeuN. However, vacuolated motoneurons, a typical signature of older clinically symptomatic Wobbler mice, were absent in the spinal cord of PND 6 Wobblers. The results suggest predominance of neuroinflammation and abnormalities of microglia and astrocytes at this early period of Wobbler life, accompanied by some neuronal changes. Data support the non-cell autonomous hypothesis of the Wobbler disorder, and bring useful information with regard to intervening molecular inflammatory mechanisms at the beginning stage of human motoneuron degenerative diseases.
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This work was supported by grants from the National Research Council of Argentina (PIP 2017-2019 #11220170100002CO and PIP 2017-2019 # 11220170100301CO), the Ministry of Science and Technology of Argentina (PICT 2017 Nº 1150 and PICT 2019 Nº 3292), the University of Buenos Aires (#20020170100224BA) and Rene Baron, Williams and Roemmers Foundations of Argentina. These funding sources did not have a role in the collection or analysis of data, writing of this manuscript or submission for publication.
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MM and MCGD performed the experiments, carried out statistical analysis, and made substantial contributions to interpretation of the data. AL provided technical support. MCGD and AFDeN designed the experiments and performed writing and editing of the manuscript. All authors read and approved the final manuscript.
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Meyer, M., Lima, A., Deniselle, M.C.G. et al. Early Signs of Neuroinflammation in the Postnatal Wobbler Mouse Model of Amyotrophic Lateral Sclerosis. Cell Mol Neurobiol 43, 2149–2163 (2023). https://doi.org/10.1007/s10571-022-01294-5
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DOI: https://doi.org/10.1007/s10571-022-01294-5