Alteration of mouse cerebellar circuits following methylazoxymethanol treatment during development: Immunohistochemistry of GABAergic elements and electron microscopic study

Abstract

Methylazoxymethanol (MAM) injected postnatally affects cerebellar development in mice. A single injection at the fifth postnatal day produces hypogranular cerebella whereas a single injection at birth produces, in addition, a disorderly cytoarchitecture of the folium and alteration of Purkinje cell positioning (Bejar et al.: Exp. Brain Res. 57:279-285, '85). In the present study we have used immunohistochemistry with anti-GABA immune serum and electron microscopy to further characterize these alterations. In addition to the already-described nonoccupied dendritic spines of Purkinje cells both in mice injected the day of birth and or at the fifth postnatal day, we have observed, in animals injected at birth, the absence of pericellular baskets around Purkinje cells and the presence of heterologous synapses between mossy fibres and Purkinje cell dendrites. These heterologous synapses apparently disappear after postnatal day 20. By using an appropriate timing of MAM injection, different types of hypogranular cerebella, phenocopies of different mutants, can be obtained in large enough number to carry out extensive biochemical studies at each developmental age.

Immunohistochemistry with anti‐calbindin and anti‐neurofilament antibodies in the cerebellum of methylazoxymethanol‐treated mice

“…In our case one might suggest that, if this modulatory role is not impaired, the structure would persist because it remains functional. The situation is different in MAMo animals, since we already observed a great disorder of the cytoachitecture of the folium (Bkjar et al, 1985;de Barry et al, 1987): the PCs were scattered throughout the folium and no basket around the PC cell hillock was observed despite the presence of neurofilament-rich profiles near the PC soma. Our present observations complete these previous studies by confirming the malpositioning of PCs and disorientation of their dendrites; they also clearly indicate that basket cell axons, hence cell bodies, are present.…”

“…A single injection on the day of birth (MAMo animals) produces hypogranularity and a general disruption of the cytoarchitecture of the cerebellar folium (Jones et al, 1972;Bejar et al, 1985), while an injection at the fifth postnatal day (MAM5 animals) also produces hypogranularity , but the folium cytoarchitecture is preserved (Bejar et al, 1985). In a previous study (de Barry et al, 1987) we observed that the pericellular basket around the Purkinje cell (PC) body is absent in MAMo animals but still present in MAM5 animals. We did not, however, determine if the absence of the pericellular basket was due to the absence of basket cells or to the difficulty of basket cell axons reaching malpositioned PC bodies.…”

“…Alterations of the target-finding process of the growing axons, because of the general disruption of the folium structure, are not likely, since perisomatic synapses on the Purkinje cell body were observed at the ultrastructural level (de Barry et al, 1987). Alternatively, the growth of the axons collaterals that form the basket might be hindered.…”

Histological, cellular and behavioural analyses of effects of chemotherapeutic agent cyclophosphamide in the developing cerebellum

“…[12][13][14] The period of granule cell neurogenesis coincides with critical sensitivity to the environment. 15,16 Due to the unique characteristics of proliferation of GNPs postnatally, CTX may have strong toxicity on the developing cerebellum in children. Up to now, however, whether and how CTX affects progenitor cell proliferation and differentiation during the cerebellar development have not been determined.…”

Distribution of metabotropic glutamate receptor type 1a in Purkinje cell dendritic spines is independent of the presence of presynaptic parallel fibers

“…Depending on the time of MAM administration, a different number of granule cells is eliminated with a proportional loss of parallel fibers. The hypogranular cerebellum, resulting from a single injection of MAM at birth (MAM 0 ), exhibits extensive cytoarchitectural disorder, altered nerve circuitry associated with cell malpositioning and ectopia, and absence of lamination similar to what occurs in granule cell-deficient mutants and to rodents treated at early postnatal ages with X-ray, virus, or antimitotic compounds (de Barry et al, 1987;Chen and Hillman, 1988;Hillman et al, 1988;de Barry and Gombos, 1989). The altered morphology is associated with neurotransmitter/receptor alterations (Johnston and Coyle, 1980;Olson et al, 1987;Bacon et al, 1989;Makowiec et al, 1991).…”