methylazoxymethanol and Cerebellar-Diseases

This review examines neuroanatomical and functional alterations in rodents resulting from postnatal insults during cerebellar development. Treatments such as irradiation and methylazoxymethanol (MAM) administration produced near birth (< postnatal day 8 for irradiation treatment and < postnatal day 4 for MAM administration) result in more severe cerebellar damage than do similar treatments administered several days after birth. Prominent among the more severe alterations are foliation abnormalities, misalignment of Purkinje cells and continued multiple innervation of climbing fibers; few or none of these occur as a result of later treatments (> postnatal day 8 for irradiation treatment and > postnatal day 4 for MAM treatment). The functional alterations also differ: insults produced near birth result in hypoactivity, ataxia, tremor and accompanying learning deficits, whereas those produced later result in hyperactivity and few learning deficits. This hyperactivity may have relevance to human disorders. Brief discussions of cerebellar and functional alterations (e.g., hyperactivity) resulting from neonatal infection with the Borna disease virus and induction of hypo- and hyperthyroidism during the preweaning period are also presented.

Topics: Animals; Animals, Newborn; Borna Disease; Cerebellar Diseases; Cerebellum; Methylazoxymethanol Acetate; Mice; Rats; Teratogens

Cerebellar pattern formation was investigated in rats treated with DNA modifying agents. Animals were subjected to combinations of daily injections of methylazoxymethanol acetate (MAM) for the last 6 days gestation and/or localised X-irradiation of the hindbrain on postnatal days 1 and 5 (P1 and P5). Animals were analysed on embryonic day 18 (E18), P0, P3, P7, and P14. Five parameters of the cerebellum were recorded from midsagittal sections: the number of primary lobules; the thickness of the external germinal layer (EGL); the density of cells in the internal granule cell layer (IGL) region; and the midsagittal area and perimeter. In addition, the laterolateral cerebellar distance was calculated. The data demonstrate that pre- and postnatal reduction of the EGL results in reduced cerebellar growth and folding. Cessation of the treatment at birth results in a recovery and eventual overproduction of EGL, but cerebellar growth and the development of fissures lags behind that of normal rats. Pre- and postnatal destruction of the EGL severely limited cerebellar growth and fissuration, and the cerebella contained only five primary lobules at P14. Rats subjected to postnatal X-irradiation alone had a similar low density of granule cells relative to those treated with a combination of prenatal MAM injections and postnatal X-irradiation, and yet the cerebella contained deeper fissures and more lobules (nine at P14). The data indicate that there are two phases of cerebellar folding: the establishment of five lobules that arise independent of granule cell production, and the granule cell-dependent expansion and partitioning of these five principal lobules during postnatal development. We propose that the lack of correlation between the severity of the granule cell loss and degree of lobulation in agranular rats indicates that granule cells exert an inductive influence over lobulation that is in part independent of the forces generated by their production and differentiation.

Topics: Abnormalities, Drug-Induced; Alkylating Agents; Animals; Cerebellar Diseases; Cerebellum; Female; Male; Methylazoxymethanol Acetate; Pregnancy; Prenatal Exposure Delayed Effects; Radiation Injuries, Experimental; Rats; Rats, Wistar