Pathogenesis of Methylazoxymethanol-Induced Lesions in the Postnatal Mouse Cerebellum

Abstract

Previous studies have shown that methylazoxymethanol acetate (MAM) and methylazoxymethanol glucoside (cycasin) cause destruction of differentiating cells in the postnatal mouse cerebellum. The major features of the resulting architectural disarray were Purkinje cell misalignment and granule cell deletion along with cerebellar dysfunction. Although it was clear from a number of studies that destruction of differentiating cells in the immediate postnatal period was the primary lesion, several important facets of the pathogenesis of the lesions remained unexplained. For example, the cellular response to the injury was incompletely described. The relationship of the cellular response to the subsequent pathological alterations was not completely evaluated. Also, the presence of unattached Purkinje cell dendritic spine postsynaptic sites suggested that their development had occurred without presynaptic parallel fiber terminal differentiation. The possibility of early synaptogenesis and degeneration was not, however, completely ruled out. In this study, the early reaction to MAM-induced differentiating cell necrosis and its relationship to the resulting abnormal cerebellar architecture was evaluated. Concomitantly, an attempt was made to clarify whether Purkinje cell postsynaptic sites differentiated with certainty in the absence of parallel fiber contacts or resulted from selective degeneration of previously formed synaptic contacts. As in previous studies, cellular necrosis and a wide range of nuclear and cytoplasmic alterations in the differentiating cells of the cerebellum were demonstrated within forty-eight hours following MAM administration. Many necrotic elements were engulfed by astrocytes, by unaffected undifferentiated cells or by macrophages. Necrotic debris was rapidly and completely cleared by five days after treatment. Response to the injury induced by MAM was, largely confined to in situ cellular elements. The destruction and repair of the differentiating cells contributed to the pattern of the altered architecture regularly observed following MAM-induced injury to the postnatal cerebellum. Except for their abnormal orientation, Purkinje cells showed no significant alterations. Astrocytic reaction rather than destruction of differentiating cells appeared to be primarily responsible for Purkinje cell misalignment. A few undisturbed parallel fiber-Purkinje cell contacts were identified by electron microscopic study indicating earlier differentiation than described elsewhere. No evidence of presynaptic degeneration was, however, present.