DEVELOPMENTAL-CHANGES IN CEREBELLAR ENDOTHELIN-1 RECEPTORS IN THE NEUROLOGIC MOUSE LURCHER MUTANT

In order to elucidate the role of neuromodulator endothein-1 (ET-1) in cerebellar degeneration we determined ET-1 receptor binding in the co ntrol and lurcher mice cerebella at different postnatal (P) ages. The lurcher mutant is a suggested animal model for human cerebellar ataxia s. The cerebellar membranes were prepared from 5 to 20 day old lurcher mice and littermate controls. ET-1 receptor binding was determined us ing radioligand assay and affinity cross-linking. There was a signific ant decrease in [I-125] ET- 1 receptor binding with increasing postnat al age in the control and lurcher mice cerebella. Lurcher mice showed a significant increase in [I-125] ET-1 receptor binding at P 9 to P 20 as compared with the controls. Whereas, at P5 to P7 no significant ch ange was observed. By autoradiography, ET-1 receptors were localized i n the granule cell layer of 15 day old control and lurcher mice cerebe lla. Whereas, the lurcher mice showed an increase in [I-125] ET-1 bind ing in the cerebellum as compared with the littermate controls. The re sults of the present study suggest that the increase in ET-1 receptor binding as early as P9 (when neuronal loss is minimal) in the lurcher mutant may reflect upregulation of ET-1 receptors in the degenerating neurons. At P 15 to P 20, when about 50% to 75% neurons are lost respe ctively, these changes may also reflect astrogliosis.