Ser133Ala mice exhibit normal levels of CREB-binding and gene transcription. Chromatin immunoprecipitation revealed normal levels of CREB enrichment at the cfos (A) F(2,13) = 49.01, P < 0.0001; S133WT, S133A Mutant versus Control, P < 0.0001; S133WT versus S133A Mutant, NS) and fosB (B) F(2,13) = 22.38, P < 0.0001; S133WT, S133A Mutant versus Control, P < 0.01; S133WT versus S133A Mutant, NS) promoter regions, with no significant differences between Ser133Ala mice and controls. Normal levels of HK3K4me3 enrichment at the cfos (C) F(2,13) = 15.32, P = 0.0009; S133WT, S133A Mutant versus Control, P < 0.01; S133WT versus S133A Mutant, NS) and fosB (D) F(2,13) = 21.40, P = 0.0004; S133WT, S133A Mutant versus Control, P < 0.01; S133WT versus S133A Mutant, NS) promoter in Ser133Ala mutant mice indicate a transcriptionally permissive state. Fear conditioning leads to a significant increase in Nr4a1 (E) N = 5–8; FINTERACTION (3,42) = 6.056, P = 0.0016, S133 WT, S133A Mutant, CREBαΔ Fear versus Control, P < 0.001; CREBαΔ versus Control, NS), Nr4a2 (F) N = 5–8; FINTERACTION (3,44) = 9.566, P < 0.0001, S133 WT, S133A Mutant, CREBαΔ Fear versus Control, P < 0.0001; CREBαΔ versus Control, NS), and cfos (G) N = 5–8; FINTERACTION (3,44) = 5.87, P = 0.006, S133 WT, S133A Mutant, CREBαΔ Fear versus Control, P < 0.0001; CREBαΔ versus Control, NS) hippocampal gene expression in both wild-type and Ser133Ala mice but not CREBαΔ mutant mice. (**) P < 0.01, (***) P < 0.001 compared with tissue taken from naïve controls. Global expression profiling of hippocampal lysates from S133A versus wild-type mice revealed no significant alterations in any individual gene on the microarray (H).