The present report describes the natural history of defective cerebellar fissuration in the rat after neonatal treatment with 6-hydroxydopamine (6-OHDA). Within 24 hours after an intracisternal (IC) injection of 100 micrograms 6-OHDA cerebellar pial fibroblasts degenerated almost completely and were phagocytosed b macrophages within 2-5 days postinjection (dpi) leaving the cerebellar surface denuded of pia. Bergmann glia end feet at first exhibited morphological signs of gliosis and later formed new sprouts that penetrated the basal lamina and grew into the subarachnoid space covering regenerating pial fibroblasts and also invading ectopic colonies of external granular layer (EGL) cells. Breaches in the basal lamina appeared after the pial fibroblast had been destroyed and were confined to areas where Bergmann glia end feet were absent and where EGL cells were opposed to the basal lamina. EGL cells escaped through these fractures into the subarachnoid space in the fissures, where they proliferated to form large colonies of granule and stellate cells. In those fissures in which EGL ectopia featured, opposing folia fused and fissures were lost. These findings suggest that pial fibroblasts and the basal lamina have an important role in maintaining lobular partition during development of the cerebellum, in establishing cerebellar fissures, and in consolidating Bergmann glia-EGL cell relationships as a prerequisite for orderly migration of EGL cells.

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Spontaneous oxygen consumption by 5,6-and 5,7-DHT (dihydroxytryptamine), reiated indoleethylamines, and 6-hydroxydopamine and oxygen consumption by these compounds in the presence of rat liver mitochondria were measured by the polarographic oxygen electrode technique. 5,6-and 5,7-DHT react with oxygen at very different rates (2.7 nmol O,/min and 33.4 nrnol O,/min, respectively) when incubated in buffer, pH 7.2, at a concentration of 1 mM and with different kinetic characteristics. While the oxidation of 5,7-DHT obeys a reaction of second-order type, the oxidation of 5,6-DHT is more complex and characterized by autocatalytic promotion. Colowed quinoidal oxidation products appeared during the degradation of both indoleamines. Glutathione, ascorbate, dithiothreitol, cysteine, albumin, and superoxide dismutase partially prevented 5,6-and 5,7-DHT from oxidative destruction. Catalase saved oxygen only in the case of 5,6-DHT by recycling of 0, released from near-stoichiometrically formed H20, during oxidation of 5,6-DHT.' 5,7-DHT did not generate H,O, in measurable amounts. Oxygen consumption rates of 5,6-and 5,7-DHT were enhanced after addition of rat liver mitochondria to the incubation medium; this resulted in an accelerated formation of quinoidal products. This stimulatory effect on the oxidation rates of both 5,6-and 5,7-DHT was blocked by cyanide, but not rotenone, and was abolished by boiling of the mitochondria fraction. The observed increase in oxygen consumption in the presence of mitochondria was found not to be influenced by monoamine oxidase-dependent deamination of 5,6-and 5,7-DHT. It is postulated that 5,6-and 5,7-DHT are capable of participating in the electron transfer of the mitochondria1 respiration chain beyond complex 111. Results obtained in determinations of ADP:O ratios in respiratory control experiments exclude a possible interference of 5,6-DHT, 5,7-DHT, and 6-OH-DA with phosphorylating sites. During the activated state of respiration, no signs of electron transfer inhibition by 5,6-and 5,7-DHT were detectable. A comparison and evaluation of the autoxidation rates of various hydroxylated indoleethylamines, of their affinity to the 5-HT transport sites, and their neurotoxic potency in vivo reveals that interaction of these compounds with oxygen at restricted reaction velocity is a prerequisite for efficient toxicity in monoaminergic neurons following active accumulation in these neurons via the high-affinity uptake systems.