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Ultrastructural characterization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death in embryonic dopaminergic neurons

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Abstract

Developing neuronal populations undergo significant attrition by natural cell death. Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis during synaptogenesis. Following this time window, destruction of the anatomic target of dopaminergic neurons results in dopaminergic cell death but the morphology is no longer apoptotic. We describe ultrastructural changes that appear unique to dying embryonic dopaminergic neurons. In primary cultures of mesencephalon, death of dopaminergic neurons is triggered by activation of glutamate receptors sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and differs ultrastructurally from both neuronal apoptosis or typical excitotoxicity. AMPA causes morphological changes selectively in dopaminergic neurons, without affecting other neurons in the same culture dishes. Two hours after the onset of treatment swelling of Golgi complexes is apparent. At 3 h, dopaminergic neurons display loss of membrane asymmetry (coinciding with commitment to die), as well as nuclear membrane invagination, irregular aggregation of chromatin, and mitochondrial swelling. Nuclear changes continue to worsen until loss of cytoplasmic structures and cell death begins to occur after 12 h. These changes are different from those described in neurons undergoing either apoptosis or excitotoxic death, but are similar to ultrastructural changes observed in spontaneous death of dopaminergic neurons in the natural mutant weaver mouse.

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Authors and Affiliations

  1. Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri

    D. A. Dorsey, D. H. Mascó, K. Dikranian, L. Masciotra, A. A. Gru & G. A. de Erausquin MD, PhD (Assistant Professor)

  2. Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA

    K. Hyrc & G. A. de Erausquin MD, PhD (Assistant Professor)

  3. Department of Otolaryngology, Washington University School of Medicine, St Louis, Missouri

    B. Faddis

  4. Departamento de Biología Celular, Universidad de Valencia, Valencia, Spain

    M. Soriano & M. P. Goldberg

  5. Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA

    M. P. Goldberg & G. A. de Erausquin MD, PhD (Assistant Professor)

  6. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba

    D. H. Mascó

  7. Psychiatry and Neurology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8134, St Louis, MO, 63110

    G. A. de Erausquin MD, PhD (Assistant Professor)

Authors
  1. D. A. Dorsey
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  2. D. H. Mascó
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  3. K. Dikranian
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  4. K. Hyrc
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  7. M. Soriano
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  8. A. A. Gru
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  10. G. A. de Erausquin MD, PhD
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Correspondence to G. A. de Erausquin MD, PhD.

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Dorsey, D.A., Mascó, D.H., Dikranian, K. et al. Ultrastructural characterization of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death in embryonic dopaminergic neurons. Apoptosis 11, 535–544 (2006). https://doi.org/10.1007/s10495-006-5268-y

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