Fig. 2: APOE4 drives early intrinsic hyperexcitability and atrophy in CA3 PCs.
a, Representative whole-cell current-clamp recordings of membrane potential response (top) to a 1-second, 150-pA suprathreshold depolarizing current injection (bottom) in CA3 PCs from young E3-KI and E4-KI mice. b, Mean input current–firing rate relationship (I–F curves), the number of spikes elicited by 1-second epochs of incremental 50-pA depolarizing current injection. c, Output gain values, quantified as the linear slope of the I–F curve. d, Rheobase values, representing the minimum 1-second depolarizing current required to elicit an AP. e, Example whole-cell current-clamp recording of spike latency protocol with membrane potential (top) response to a ramped 800-pA, 1-second depolarizing current injection (bottom). f, Spike latency values. g, Cell Cm values. h, Rin values. i, Cell soma volumes for CA3 PCs from young E3-KI and E4-KI mice, measured directly or predicted using reported specific Cm of 0.9 pF cm−2. Statistical differences were analyzed using the Kolmogorov–Smirnov test. j, Correlation between Cm and Rin values in young E3-KI (blue) and E4-KI (red) CA3 PCs. Numbers represent Pearson’s correlation coefficient and corresponding P values. k–m, Cell Cm correlates with neuronal excitability in E4-KI but not in E3-KI neurons: correlation between Cm and output gain (k), rheobase (l) and spike latency (m). Pearson’s correlation analysis (two-sided). All data are represented as mean ± s.e.m. For all panels: young E3-KI: eight mice, n = 37 cells (36 in f); young E4-KI: seven mice, n = 25 cells; aged E3-KI: six mice, n = 24 cells; aged E4-KI: four mice, n = 21 cells. Significance was assessed using a maximum likelihood ratio test that included age and APOE genotype, with P values corrected for multiple comparisons using the FDR (5%). Post hoc unpaired two-tailed Student’s t-tests or Mann–Whitney U-tests were performed between groups if significant genotype or age effects were observed.
