Exaggerated cyclic AMP accumulation and glial cell reaction in the cerebellum during Purkinje cell degeneration in pcd mutant mice.
The Purkinje cell degeneration mutant (pcd) is characterized by a complete loss of cerebellar Purkinje cells. Norepinephrine causes an accumulation of cyclic AMP in the cerebellum of pcd that is far greater than in normal mice. Experiments were conducted 1) to correlated changes in the cyclic-nucleotide response with a histologic examination of the cerebellum during neuronal loss and 2) to examine the role of cyclic AMP catabolism and adenosine receptor interactions in the phenomenon. The greatest elevation in cyclic AMP occurred between 30 and 128 days of age when a severe astrocytic response was demonstrated throughout the cerebellar cortex. Purkinje cells had degenerated by 45 days of age. Norepinephrine elicited a smaller increase in cyclic AMP from 155-day-old mice than at earlier ages, and the response continued to decrease with age; at 270 days, equal accumulation, and at 365 days. lower accumulation of cyclic AMP was detected in pcd cerebella. During this time, the Purkinje cell debris had been removed, the granule cell layer was depleted of granule cells, and the molecular layer was deprived of a large number of parallel fibers. However, although phagocytosis of neuronal debris was completed, large numbers of astrocytic processes were still seen in the neuropil. Biochemical experiments in vitro established that the exaggerated accumulation of cyclic AMP in the presence of norepinephrine was not due to lower catabolism of cyclic AMP, a synergistic interaction with adenosine, or a result of lower protein in the pcd cerebellum. The correlates of heightened norepinephrine-stimulated accumulation of cyclic AMP with neuronal loss and the glial cell reaction might indicate that cyclic nucleotides play a role in controlling some glial cell functions, ie, proliferation, migration, and phagocytosis.
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002525:Cerebellar Cortex / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D051379:Mice; D008818:Mice, Neurologic Mutants; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000187:drug effects; D009457:Neuroglia / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011689:Purkinje Cells / Q000378:metabolism*
D000242:Cyclic AMP; D009638:Norepinephrine