Reorganization of the rat cerebellar cortex during postnatal development following cisplatin treatment.
We examined the effects of the antitumor agent cisplatin on the development and plasticity of cerebellar cytoarchitecture. Since knowledge of the parallel and climbing fiber-Purkinje cell system is important in order to determine the architectural basis of cerebellar function, we used immunofluorescence for vesicular glutamate transporters (VGluT1 and VGluT2) to evaluate the trend of synaptogenesis of parallel and climbing fibers on Purkinje cells in the cerebellum vermis after a single injection of cisplatin to 10-day-old rats, i.e., during a crucial period of cerebellar development. The temporal and spatial patterns of VGluT1 and VGluT2 immunoreactivity after the early cisplatin injury provided evidence that remodeling of excitatory afferents and Purkinje cell dendrites occurs. After an early slow down of Purkinje cell dendrite growth, 7 days following the treatment, the extension of the molecular layer was reduced, as was parallel fiber innervation, but VGluT1 immunoreactive fibers contacted Purkinje cell dendrite branches extending within the external granular layer. VGluT2 immunopositive climbing fiber varicosities were still largely present on the soma and stem dendrites of Purkinje cells. Twenty days after the cisplatin injection, the thickness of the VGluT1 immunopositive molecular layer was reduced. VGluT2 climbing fiber varicosities were found on the remodeled Purkinje cell dendrites, as in controls, although at a lower density. Alterations in the immunoreactivity for polysialic acid neural cell adhesion molecule (PSA-NCAM) during the recovery phase suggest that this molecule plays a fundamental role not only during development, but also in the reorganization of neuroarchitecture. The changes were restricted to the neocerebellar vermis and were likely dependent on the different timing of lobule formation. The results of these investigations reveal the existence of vulnerability windows of the cerebellum to exposure to experimental or environmental cytotoxic agents during a critical period in development.
Avella
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Dipartimento di Biologia Animale, Lab. Biologia Cellulare e Neurobiologia, Piazza Botta 10, 27100 Pavia, Italy.
Pisu
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MB
Roda
E
E
Gravati
M
M
Bernocchi
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D064026:Calbindins; D002525:Cerebellar Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D015151:Immunoblotting; D007150:Immunohistochemistry / Q000379:methods; D007279:Injections, Subcutaneous; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D012794:Sialic Acids / Q000378:metabolism; D013997:Time Factors; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
D000970:Antineoplastic Agents; D064026:Calbindins; D039842:Neural Cell Adhesion Molecule L1; D064030:S100 Calcium Binding Protein G; D012794:Sialic Acids; C493475:Slc17a6 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; C103469:polysialyl neural cell adhesion molecule; D002945:Cisplatin