Cerebellar Purkinje cell loss in aging Hu-Bcl-2 transgenic mice

J Comp Neurol. 2004 Aug 2;475(4):481-92. doi: 10.1002/cne.20196.

Abstract

The number of cerebellar Purkinje cells is increased by over 40% in young transgenic mice that overexpress a human Bcl-2 transgene (Hu-Bcl-2). To determine whether the Bcl-2-mediated rescue of Purkinje cells persists through life, the numbers of Purkinje cells were estimated in 6-, 12-, 18-, and 24-month-old Hu-Bcl-2 transgenic mice and age-matched controls. In addition, the expression of four markers for Purkinje cell differentiation, calbindin (CaBP), the 67-kDa isoform of glutamic acid decarboxylase (GAD67), gamma-aminobutyric acid transaminase (GABA-T), and the NMDA-R1 receptor subtype (NMDA-NR1) was analyzed in 6-month-old Hu-Bcl-2 transgenics and controls to determine whether overexpression of Bcl-2 and rescue from naturally occurring cell death affects the normal differentiation of Purkinje cells. The estimates of Purkinje cell numbers showed that the number of Purkinje cells in the Hu-Bcl-2 transgenics declines after 6 months to approach wild-type values by 18 months. Although the exogenous human BCL-2 is still expressed in Purkinje cells at 24 months, the expression levels of human BCL-2 appear to decline significantly after 6 months, suggesting that survival of the supernumary Purkinje cells depends on the sustained overexpression of Bcl-2. All the Purkinje cells in the Hu-Bcl-2 transgenic mice appeared to express normal levels of the differentiation markers analyzed so there was no evidence for a class of Purkinje cells that do not differentiate normally when rescued from naturally occurring cell death.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Aminobutyrate Transaminase / biosynthesis
  • Aging*
  • Animals
  • Apoptosis / physiology
  • Blotting, Western
  • Calbindins
  • Cell Count
  • Cell Differentiation / physiology*
  • Glutamate Decarboxylase / biosynthesis
  • Immunohistochemistry
  • In Situ Hybridization
  • Isoenzymes / biosynthesis
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / physiology*
  • Purkinje Cells / cytology*
  • Purkinje Cells / metabolism*
  • Receptors, N-Methyl-D-Aspartate / biosynthesis
  • S100 Calcium Binding Protein G / biosynthesis

Substances

  • Calbindins
  • Isoenzymes
  • NR1 NMDA receptor
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, N-Methyl-D-Aspartate
  • S100 Calcium Binding Protein G
  • 4-Aminobutyrate Transaminase
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1