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. 2010 Dec 29;171(4):1265-72.
doi: 10.1016/j.neuroscience.2010.10.027. Epub 2010 Oct 15.

Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2

R C Klein  1 , B E Mace, S D Moore, P M Sullivan
Affiliations

Progressive loss of synaptic integrity in human apolipoprotein E4 targeted replacement mice and attenuation by apolipoprotein E2

R C Klein et al. Neuroscience. .

Abstract

Inheritance of the APOE4 allele is a well established genetic risk factor linked to the development of late onset Alzheimer's disease. As the major lipid transport protein in the central nervous system, apolipoprotein (apo) E plays an important role in the assembly and maintenance of synaptic connections. Our previous work showed that 7 month old human apoE4 targeted replacement (TR) mice displayed significant synaptic deficits in the principal neurons of the lateral amygdala, a region that is critical for memory formation and also one of the primary regions affected in Alzheimer's disease, compared to apoE3 TR mice. In the current study, we determined how age and varying APOE genotype affect synaptic integrity of amygdala neurons by comparing electrophysiological and morphometric properties in C57BL6, apoE knockout, and human apoE3, E4 and E2/4 TR mice at 1 month and 7 months. The apoE4 TR mice exhibited the lowest level of excitatory synaptic activity and dendritic arbor compared to other cohorts at both ages, and became progressively worse by 7 months. In contrast, the apoE3 TR mice exhibited the highest synaptic activity and dendritic arbor of all cohorts at both ages. C57BL6 mice displayed virtually identical synaptic activity to apoE3 TR mice at 1 month; however this activity decreased by 7 months. ApoE knockout mice exhibited a similar synaptic activity profile with apoE4 TR mice at 7 months. Consistent with previous reports that APOE2 confers protection, the apoE4-dependent deficits in excitatory activity were significantly attenuated in apoE2/4 TR mice at both ages. These findings demonstrate that expression of human apoE4 contributes to functional deficits in the amygdala very early in development and may be responsible for altering neuronal circuitry that eventually leads to cognitive and affective disorders later in life.

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Figures

Figure 1
Figure 1
A. Representative traces of whole-cell patch-clamp recordings illustrating sEPSCs in lateral amygdala neurons from designated cohorts at 7 months of age. Scale bar is 10 pA, 2 ms. B. Comparison of mean ± SEM amplitude (left) and interval (right) of sEPSCs at 7 months of age (C). No significant differences in amplitude occurred. Compared to E3/E3, significant differences in the sEPSC interval were observed in C57 (* p<0.05), E2/E4 (** p<0.005), E4/E4 and KO (*** p<0005). There was also a significant difference (p<0.01) between the E4/E4 and E2/E4 cohorts. See Table 1 for N values.
Figure 2
Figure 2
A. High power image of a representative pyramidal-like lateral amygdala neuron from an apoE3 TR mouse at 7 months of age (scale bar, 50 µm). B. Camera lucida reconstructions (left) and dendrograms (right) corresponding to representative neurons from the indicated cohorts. Quantitative morphological analysis is presented in Table 2.
Figure 3
Figure 3
Scholl analysis of averaged lateral amygdala neurons from the indicated ApoE cohort at 7 months of age representing the dendritic length and the number of dendritic intersections crossing each 10 µm radius progressively more distal to the soma. See Table 2 for N values.
Figure 4
Figure 4
Comparison of mean ± SEM amplitude (left) and interval (right) of sEPSCs at 1 month of age. The mean interval was significantly lower in apoE4 TR mice compared to apoE3 (p<0.005), apoE2/E4 (p<0.05) and C57 (p<0.01). See Table 1 for N values.
See this image and copyright information in PMC

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