Behavioural, physiological and morphological analysis of a line of apolipoprotein E knockout mouse.
Using apolipoprotein E knockout mice derived from the Maeda source [Piedrahita J. A. et al. (1992) Proc. natn. Acad Sci. US.A. 89, 4471 4475], we have studied the influence of apolipoprotein E gene deletion on normal CNS function by neurological tests and water maze learning, hippocampal ultrastructure assessed by quantitative immunocytochemistry and electron microscopy, CNS plasticity, i.e. hippocampal long-term potentiation and amygdaloid kindling, and CNS repair, i.e. synaptic recovery 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. Apolipoprotein E knockout mice aged eight months demonstrated accurate spatial learning and normal neurological function. Synaptophysin and microtubule-associated protein 2 immunohistochemistry and electron microscopic analysis of these animals revealed that the hippocampal synaptic and dendritic densities were similar between genotypes. The induction and maintenance of kindled seizures and hippocampal long-term potentiation were indistinguishable between groups. Finally, unilateral entorhinal cortex lesions produced a marked loss of hippocampal synaptophysin immunoreactivity in both groups and a marked up-regulation of apolipoprotein E in the wild-type group. Both apolipoprotein E knockout and wild-type groups showed immunohistochemical evidence of reactive synaptogenesis, although the apolipoprotein E knockout group may have initially shown greater synaptic loss. It is suggested that either apolipoprotein E is of no importance in the maintenance of synaptic integrity and in processes of CNS plasticity and repair, or more likely, alternative (apolipo)proteins may compensate for the loss of apolipoprotein E in the knockout animals.
Anderson
R
R
Neuroscience Unit, Glaxo Wellcome Research and Development, Medicines, Research Centre, Stevenage, Herts, UK.
Barnes
J C
JC
Bliss
T V
TV
Cain
D P
DP
Cambon
K
K
Davies
H A
HA
Errington
M L
ML
Fellows
L A
LA
Gray
R A
RA
Hoh
T
T
Stewart
M
M
Large
C H
CH
Higgins
G A
GA
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001522:Behavior, Animal / Q000502:physiology*; D018891:Dentate Gyrus / Q000166:cytology / Q000648:ultrastructure; D004594:Electrophysiology; D018728:Entorhinal Cortex / Q000502:physiology; D019922:GAP-43 Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D007696:Kindling, Neurologic / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout / Q000033:anatomy & histology / Q000502:physiology* / Q000523:psychology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology; D013569:Synapses / Q000648:ultrastructure; D016708:Synaptophysin / Q000378:metabolism
D001057:Apolipoproteins E; D019922:GAP-43 Protein; D008869:Microtubule-Associated Proteins; D016708:Synaptophysin