Synaptic Ultrastructural Alterations Anticipate the Development of Neuroaxonal Dystrophy in Sympathetic Ganglia of Aged and Diabetic Mice

• Published in: Journal of neuropathology and experimental neurology Vol. 67; no. 12; pp. 1166 - 1186
• Main Authors: Schmidt, Robert E, Parvin, Curtis A, Green, Karen G
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.12.2008; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Aging - pathology; Animals; Autonomic Nervous System Diseases - etiology; Autonomic Nervous System Diseases - pathology; Biological and medical sciences; Dendrites - ultrastructure; Diabetes Mellitus, Experimental - complications; Diabetic Neuropathies - etiology; Diabetic Neuropathies - pathology; Disease Models, Animal; Diseases of the osteoarticular system; Female; Ganglia, Sympathetic - ultrastructure; Image Cytometry; Intracellular Membranes - ultrastructure; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron, Transmission; Mitochondria - ultrastructure; Nerve Degeneration - etiology; Nerve Degeneration - pathology; Neurology; Phagosomes - ultrastructure; Presynaptic Terminals - ultrastructure; Synapses - ultrastructure; Synaptic Membranes - ultrastructure; Tumors of striated muscle and skeleton; Endocrinopathy; Senescence; Alteration; Neuroaxonal dystrophy; Diabetic neuropathy; Neuropathy; Autonomic nervous system; Ultrastructure; Development; Aging; Degenerative disease; Dendritic dystrophy; Nervous system diseases; Diabetes mellitus; Rodentia; Mitochondriopathy; Sympathetic nervous system; Genetic disease; Cerebral disorder; Vertebrata; Mammalia; Mouse; Animal; Central nervous system disease; Autonomic neuropathy
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e318190d6db

Neuroaxonal dystrophy, a distinctive axonopathy characterized by marked enlargement of distal axons, is the hallmark pathologic alteration in aged and diabetic human prevertebral sympathetic ganglia and in corresponding rodent models. Neuroaxonal dystrophy is thought to represent the abnormal outcome of cycles of synaptic degeneration and regeneration; a systematic study of identified axon terminals in aged and diabetic prevertebral ganglia, however, has not previously been performed. We examined the initial changes that develop in presynaptic and postsynaptic elements in sympathetic ganglia of aged and diabetic mice and found numerous synaptic changes involving both presynaptic and postsynaptic elements. Early alterations in presynaptic axon terminal size, vesicle content, and morphology culminate in the development of anastomosing membranous tubulovesicular aggregates, accumulation of autophagosomes, and amorphous debris that form a continuum with progressively larger classically dystrophic swellings. Dendritic changes consist of the development of swellings composed of delicate tubulovesicular elements and mitochondriopathy characterized by increased numbers of small mitochondria and, exclusively in aged ganglia, megamitochondria. These results support the hypothesis that neuroaxonal dystrophy results from progressive changes in presynaptic axon terminals that likely involve membrane dynamics and which are accompanied by distinctive changes in postsynaptic dendritic elements.