Consequences of apolipoprotein E isoform variation: effects on hippocampus synaptic plasticity, learning and memory in the adult mouse
Dissertation under the direction of Professor Edwin J. WEeber Apolipoprotein E (apoE) interacts with lipoprotein receptors in the hippocampus. These receptors are intimately involved in the modulation of synaptic plasticity, learning and memory. Isoform variation in apoE may differentially alter this lipoprotein receptor-dependent synaptic modulation as apoE isoforms are associated with human neurodegenerative disorders. In the present study, apoE2, apoE3 and apoE4 targeted replacement (TR) mice were used along with recombinant human apoE isoforms to determine the role of apoE isoforms in hippocampus area CA1 synaptic function. While synaptic transmission is unaffected by apoE isoform, long-term potentiation (LTP) is significantly enhanced in apoE4 TR mice versus apoE2 TR mice. ApoE isoform-dependent differences in LTP induction require NMDA-receptor function, and apoE isoform expression alters activation of both ERK1/2 and JNK1/2. Acute application of apoE isoforms similarly alters LTP induction (E4>E2) but both apoE2 and apoE4 decrease NMDA receptor mediated field potentials. Furthermore, acute apoE isoform application does not alter ERK1/2 and JNK1/2 activation like chronic apoE expression. ApoE isoforms also differentially alter learning and memory in adult male mice. ApoE TR animals were utilized to isolate the behavioral effects of apoE isoform. ApoE-deficient and C57BL/6J (wild-type) mice were tested concurrently, evaluating all in working memory, associative learning, and spatial memory. General locomotion, sensorimotor gating, and working memory were not altered by either the lack of murine apoE or the presence of human apoE isoforms. Testing of long-term contextual associative memory revealed significant differences only between apoE2 and apoE4 TR animals. ApoE4 TR animals were impaired in spatial learning while apoE3 TR animals were not. These findings demonstrate specific, isoform-dependent effects of human apoE isoforms on adult hippocampus synaptic plasticity. There may be mechanistic differences between chronic apoE isoform expression and acute apoE isoform exposure in this modulation. These findings also support the hypothesis that apoE isoforms play a specific role in modulating learning and memory.