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

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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), γ‐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. J. Comp. Neurol. 475:481–492, 2004.