a, Representative immunohistochemical images depicting HDAC2 in hippocampal area CA1 of CK-p25, shHDAC2, CK-p25, scr, and CON, scr animals; scale bar, 20μm. b, Quantitative assessment of (a), n=4-5 sections from 4 mice each. c, Quantitative PCR results of AcH4K12-immunoprecipitated chromatin in CK-p25, scr and CK-p25, shHDAC2 compared to CON, scr mice. d, Quantitative RT-PCR results of the same genes. (c, d, n=4-6 animals each). e, g, Representative immunohistochemical images depicting (c) Svp and (e) MAP2 immunoreactivity in the hippocampus stratum radiatum, scale bars c, 25μm, e, 20μm f, Quantitative assessment of (c), n=4 mice each. f, Freezing responses of CON, scr (n=18), CK-p25, scr (n=16) and CK-p25, shHDAC2 (n=16) mice 24 h after contextual fear conditioning. g, Escape latencies in a water maze task of CON, scr (n=19), CK-p25, scr (n=17) and CK-p25, shHDAC2 (n=19) animals. Data points are averages of two trials per day. h, Representative swim traces and time spent per quadrant during the water maze test (T, target quadrant, R=right, O=opposite, L=left of target). *p≤0.05; **p≤0.01; ***p≤0.001, values are mean ± s.e.m.

a-c, Representative immunohistochemical images depicting nuclear HDAC1-3 levels (white dotted circles) in neurons (arrow points to magnified neuron in inset) of hippocampal area CA1 from patients with Braak and Braak (BB) stages I/II (n=4), III/IV (n=7) and V/VI (n=8) compared to healthy BB0 control brains (CON, n=7); scale bar, 100μm. d-e, Quantitative assessment of (a-c). **p≤0.01, values are mean ± s.e.m.

a-c, Representative immunohistochemical images depicting HDAC1-3 levels in area CA1 of CK-p25 mice and control littermates (n=3-6 slices from 3-4 mice each), scale bar, 20μm. d, Quantitative assessment of (a-c). e, Representative WB images and quantification of HDAC1-3 protein in the CK-p25 and control hippocampus (n=6-9 mice each). f-h, Quantitative PCR results of (f) HDAC2-, (g) AcH4K12-, and (h) RNA Pol II-immunoprecipitated chromatin at the promoter of neuroplasticity and housekeeping genes in the CK-p25 and control hippocampus. (i), Quantitative RT-PCR results of the same genes (f-i, n=4-8 animals each). Note that for (i) Bdnf “1”, “2” and “4” represent Bdnf exons I, II and IV, respectively. *p≤0.05; **p≤0.01; ***p≤0.001, values are mean ± s.e.m.

a, c, Representative pictures of HDAC2 and PGR1 labeling of primary hippocampal neurons treated with (a) H₂O₂ and (c) Aβ-oligomers (n=20-40 neurons per group), scale bar, 10μm. b, d, Quantification of (a) and (c). e, f, Quantitative RT-PCR results showing Hdac2 expression in (e) H₂O₂- and Aβ-treated primary hippocampal neurons, and (f) in the CK-p25 hippocampus (n=7-9 mice each). g, Alignment of the vertebrate glucocorticoid responsive element (GRE) consensus sequence with the GRE in the proximal promoter of mouse Hdac2. h, Quantification and representative WB images of hippocampal extracts of CK-p25 versus control mice (n=3 each). i, Representative images of immunohistochemical labeling of PGR1 and HDAC2 in the CK-p25 hippocampus (n=3-6 slices from 3 mice each); scale bar, 20μm. j, Regression analysis of (i) showing a significant correlation between PGR1 and HDAC2 in CK-p25 (R²=0.686, p≤0.001), but not control mice (R²=0.019, n.s.). k, Quantification and representative WB images of Cdk5cKO and control Cdk5fl/fl forebrain extracts (n=3 each). l, Quantitative PCR results of PGR1-immunoprecipitated chromatin around the GRE in a 1.3 kb-wide Hdac2 promoter region (schematically shown above the graph; TSS, transcriptional start site) in the CK-p25 and control hippocampus (n=3-6 animals each); green lines represent fragments amplified by primer pairs. m, Luciferase activity of CAD cells transfected with the Hdac2 promoter with (orange) or without (blue) GRE (schematic of constructs shown above graph), and treated with H₂O₂ and Aβ_1-42. n, Luciferase activity of CAD cells transfected with Hdac2-GRE in the presence of endogenous GR or of cotransfected GRS211A. In vitro results are from ≥3 independent experiments. *p≤0.05; **p≤0.01; ***p≤0.001, values are mean ± s.e.m.