Signal molecules and receptors in the differential development of cerebellum lobules. Acute effects of cisplatin on nitric oxide and glutamate systems in Purkinje cell population.

Three functionally correlated parameters, nitric oxide (NO), glutamate and NMDA receptors were analyzed through enzymehistochemical and immunohistochemical reactions. A single injection of cisplatin (cisPt) was administered to 10-day-old rats in order to study how Purkinje cells differentiation may be early changed by a mild injury due to the drug during postnatal cerebellar histogenesis. In comparison with age-matched control rats, a correlated decreasing expression of nitric oxide synthase (NOS), glutamate and NMDAR1 was observed in the Purkinje cells of lobules VI-VIII 6 h after the treatment. Moreover, at 24 h after cisPt, the expression of glutamate, NMDAR1 and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPHd) reactivity was further decreased. In the same period, the ionotropic receptor GluR2 evidenced a less developed dendrite of Purkinje neurons in the top of lobules. In addition, the metabotropic receptor mGluR1alpha revealed unstained areas in the molecular layer, which was entirely stained in control rats; on PD11 this altered pattern was observed in all the lobules and in both the outer and the inner parts. Findings show the importance of NO-glutamate interactions via NMDAR1 in the crucial phases of Purkinje cells differentiation and their involvement on Purkinje neurons dendrite branching as demonstrated by the patterns of the other glutamate receptors. Changes were discussed in relation to an important critical event of Purkinje cell differentiation, i.e. regression of perisomatic spines and elimination of climbing fiber synapses on the somata. Finally, lobules VI-VIII appear to be the most vulnerable ones when cisplatin treatment is administered at 10 days of life, which demonstrates that at this stage some critical developmental changes occur in these lobules and that slower/damaged dendritic tree development is different in the outer versus the inner regions of the lobules.