title: Cerebellar benzodiazepine receptors: cellular localization and consequences of neurological mutations in mice.
abstract: The distribution of cerebellar [3H]flunitrazepam binding sites was studied autoradiographically in Purkinje cell degeneration (pcd/pcd), weaver (wv/wv), staggerer (sg/sg) and reeler (rl/rl) mutant mice. In the normal 78-day-old C57BL/6J mouse cerebellum, the highest concentration of [3H]flunitrazepam binding sites was observed over the molecular layer. Intermediate grain density was present over the Purkinje cell layer and intermediate to high density over the deep cerebellar nuclei. Low labeling was observed over the granule cell layer. Negligible concentrations of binding sites were seen in the white matter. In 45-49-day-old Purkinje cell degeneration mutants, where essentially all Purkinje cells have disappeared by day 45, there was a small decrease in grain density over the cerebellar cortex. Concomitantly, a substantial increase in grain density was observed over the deep cerebellar nuclei of the pcd/pcd mutants when compared to littermate controls. A significant increase in [3H]flunitrazepam labeling was observed over the cerebellar cortex of 81-86-day-old wv/wv mutants; this was most pronounced in the vermis where the granule cell loss was greatest. Over the hemispheres, where fewer granule cells degenerate, a lower density of binding sites was seen. Grain density over the wv/wv deep cerebellar nuclei was comparable to that of littermates. Substantially lower [3H]flunitrazepam labeling was detected over the cerebellar cortex of 25-27-day-old sg/sg mutants in which the number of granule, Purkinje and Golgi cells is greatly reduced; the labeling over the deep nuclei, however, was significantly increased. In 27-29-day-old rl/rl mutant cerebella, where all classes of cells are malpositioned, labeling density over all areas of the cerebellar cortex, including the Purkinje cell masses, was increased. Our autoradiographic data suggest that a proportion of cerebellar cortical benzodiazepine receptors are associated with Purkinje cells; we propose that the remainder of the receptors are localized on Golgi cells, while granule cells are devoid of receptors. In the deep cerebellar nuclei, the observed increase in benzodiazepine receptors in the pcd/pcd and sg/sg mutants may be a manifestation of denervation supersensitivity subsequent to the loss of innervation by Purkinje cell axon terminals. The finding of a high receptor density in the Purkinje cell masses of the rl/rl mutant, where Purkinje cells are devoid of afferent basket cell input, suggests that benzodiazepine receptors are expressed and maintained in the absence of a full complement of GABAergic afferents.
authors.affiliation: Department of Pharmacology, California College of Medicine, University of California, Irvine 92717.
authors.forename: A
authors.initials: A
authors.lastname: Rotter
authors.forename: A
authors.initials: A
authors.lastname: Frostholm
mesh_terms: D000818:Animals; D001345:Autoradiography; D002531:Cerebellum / Q000378:metabolism*; D005445:Flunitrazepam / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation; D011689:Purkinje Cells / Q000378:metabolism / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D012016:Reference Values; D014316:Tritium
chemical_list: D011963:Receptors, GABA-A; D014316:Tritium; D005445:Flunitrazepam