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The Journal of Neuroscience, October 15, 2001, 21(20):8072-8081

Long-Lasting Aberrant Tubulovesicular Membrane Inclusions Accumulate in Developing Motoneurons after a Sublethal Excitotoxic Insult: A Possible Model for Neuronal Pathology in Neurodegenerative Disease

Olga Tarabal¹, Jordi Calderó¹, Jerònia Lladó¹, Ronald W. Oppenheim², and Josep E. Esquerda¹

¹ Unitat de Neurobiologia Cellular, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, E25198 Lleida, Catalonia, Spain, and ² Department of Neurobiology and Anatomy and Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

We have previously shown that chronic treatment of chick embryos [from embryonic day 5 (E5) to E9] with NMDA rescues spinal cord motoneurons (MNs) from programmed cell death. In this situation, MNs exhibit a reduced vulnerability to acute excitotoxic lesions and downregulate NMDA and AMPA-kainate receptors. Here, we report that this treatment results in long-lasting sublethal structural changes in MNs. In Nissl-stained sections from the spinal cord of NMDA-treated embryos, MNs display an area adjacent to an eccentrically positioned nucleus in which basophilia is excluded. Ultrastructurally, MNs accumulate tubulovesicular structures surrounded by Golgi stacks. Thiamine pyrophosphatase but not acid phosphatase was detected inside the tubulovesicular structures, which are resistant to disruption by brefeldin A or monensin. Immunocytochemistry reveals changes in the content and distribution of calcitonin gene-related peptide, the KDEL receptor, the early endosomal marker EEA1, and the recycling endosome marker Rab11, indicating that a dysfunction in membrane trafficking and protein sorting occurs in these MNs. FM1-43, a marker of the endocytic pathway, strongly accumulates in MNs from isolated spinal cords after chronic NMDA treatment. Changes in the distribution of cystatin C and presenilin-1 and an accumulation of amyloid precursor protein and -amyloid product were also observed in NMDA-treated MNs. None of these alterations involve an interruption of MN-target (muscle) connections, as detected by the retrograde tracing of MNs with cholera toxin B subunit. These results demonstrate that chronic NMDA treatment induces severe changes in the motoneuronal endomembrane system that may be related to some neuropathological alterations described in human MN disease.

Key words: ALS; autophagy; chick embryo; Golgi apparatus; glutamate receptor-mediated excitotoxicity; membrane traffic; motoneuron

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21208072-10$05.00/0

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