title: Spatiotemporal analysis of purkinje cell degeneration relative to parasagittal expression domains in a model of neonatal viral infection.
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 for several models of early-life viral infection, including NBD; however, the time course and distribution of PC pathology have not been investigated rigorously. This study examined the spatiotemporal relationship between PC death and zonal organization in NBD cerebella. Real-time PCR at postnatal day 28 (PND28) revealed decreased cerebellar levels of mRNAs encoding the glycolytic enzymes aldolase C (AldoC, also known as zebrin II) and phosphofructokinase 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 densities of microglia and the Bergmann glial expression of metallothionein I/II and the hyaluronan receptor CD44 were 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 the loss of both zebrin II/EAAT4-negative and 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 a differential vulnerability of PC subsets during the early stages of virus-induced neurodegeneration.
authors.affiliation: Jerome L. and Dawn Greene Infectious Disease Laboratory, Mailman School of Public Health, Columbia University, 722 West 168th Street, Rm. 1801, New York, NY 10032, USA.
authors.forename: Brent L
authors.initials: BL
authors.lastname: Williams
authors.forename: Kavitha
authors.initials: K
authors.lastname: Yaddanapudi
authors.forename: Mady
authors.initials: M
authors.lastname: Hornig
authors.forename: W Ian
authors.initials: WI
authors.lastname: Lipkin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001890:Borna Disease / Q000378:metabolism* / Q000473:pathology; D001891:Borna disease virus; D064026:Calbindins; D016923:Cell Death; D002531:Cerebellum / Q000503:physiopathology; D050581:Excitatory Amino Acid Transporter 4 / Q000032:analysis / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D007700:Kinetics; D008959:Models, Neurological; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D025502:Phosphofructokinase-1, Type C / Q000032:analysis / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011689:Purkinje Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D064030:S100 Calcium Binding Protein G / Q000378:metabolism
chemical_list: D064026:Calbindins; D050581:Excitatory Amino Acid Transporter 4; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; C493389:Slc1a6 protein, rat; C071871:zebrin II; D025502:Phosphofructokinase-1, Type C