BEHAVIORAL, PHYSIOLOGICAL AND MORPHOLOGICAL ANALYSIS OF A LINE OF APOLIPOPROTEIN-E KNOCKOUT MOUSE

Using apolipoprotein E knockout mice derived from the Maeda source [Pi edrahita J. A. et al. (1992) Proc. natn. Acnd. Sci U.S.A. 89, 4471-447 5], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hi ppocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term po tentiation and amygdaloid kindling, and CNS repair, i.e. synaptic reco very in the hippocampus following deafferentation. In each study there was little difference between the apolipoprotein E knockout mice and wild-type controls of similar age and genetic background. Apolipoprote in E knockout mice aged eight months demonstrated accurate spatial lea rning and normal neurological function. Synaptophysin and microtubule- associated protein 2 immunohistochemistry and electron microscopic ana lysis of these animals revealed that the hippocampal synaptic and dend ritic densities were similar between genotypes. The induction and main tenance of kindled seizures and hippocampal long-term potentiation wer e indistinguishable between groups. Finally, unilateral entorhinal cor tex lesions produced a marked loss of hippocampal synaptophysin immuno reactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-typ e groups showed immunohistochemical evidence of reactive synaptogenesi s, although the apolipoprotein E knockout group may have initially sho wn greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in p rocesses of CNS plasticity and repair, or more likely, alternative (ap olipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals. (C) 1998 IBRO. Published by Elsevier Science Ltd.