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J. Virol. doi:10.1128/JVI.02245-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Spatiotemporal Analysis of Purkinje Cell Degeneration Relative to Parasagittal Expression Domains in a Model of Neonatal Viral Infection

Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health, Columbia University, New York, NY

^* To whom correspondence should be addressed. Email: wil2001{at}columbia.edu.

	Abstract

Infection of newborn Lewis rats with Borna disease virus (Neonatal borna disease, NBD) results in cerebellar damage without the cellular inflammation associated with infections in later life. Purkinje cell (PC) damage has been reported in several models of early life viral infection including NBD; however, the time course and distribution of PC pathology has not been rigorously investigated. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at PND28 revealed decreased cerebellar levels of mRNA encoding glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase-C (PFK-C), and the excitatory amino acid transporter 4 (EAAT4). Zebrin II and EAAT4 immunofluorescence analysis in PND21, PND28, PND42, and PND84 NBD rat cerebella revealed a complex pattern of PC degeneration. Early cell loss (PND28) was characterized by preferential apoptotic loss of zebrin II/EAAT4-negative PC subsets in the anterior vermis. Consistent with early preferential loss of zebrin II/EAAT4-negative PCs in the vermis, the density of microglia and Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 was higher in zebrin II/EAAT4-negative zones. In contrast, early loss in lateral cerebellar lobules did not reflect a similar discrimination between PC phenotypes. Patterns of vermal PC loss became more heterogeneous at PND42 with loss of both zebrin II/EAAT4-negative as well as zebrin II/EAAT4-positive neurons. At PND84, zebrin II/EAAT4 patterning was abolished in the anterior cerebellum, with preferential PC survival in lobule X. Our investigation reveals regional discrimination between patterns of PC subset loss, defined by zebrin II/EAAT4 expression domains, following neonatal viral infection. These findings suggest differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.

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