a, Stereotactic surgery was performed to deliver AAV9 knockdown vector into the dorsal hippocampus (AP, −2.0 mm; DV, −1.4 mm; ML, ±1.5 mm from bregma); 4 weeks later, habituated mice were trained in object location memory (OLM; four 5-min training sessions in arena with three different objects). Twenty-four hours later the mice were given a retention test in which one object was moved to a novel location (n = 10 per cohort). b, Western blot analysis of hippocampal tissue removed from mice injected into the dorsal (d) or ventral (v) hippocampus with either eGFP control or ACSS2 knockdown vector shows specific reduction of ACSS2 in dorsal hippocampus. c, ACSS2-knockdown mice are impaired in object location memory. eGFP control and shACSS2 AAV9 mice display no preference for any of three objects (O1–3) during the object location memory training session (TR). In the retention test 24 h later, control mice show a preference for the novel object location (NL), whereas the knockdown mice display no such preference. ***P < 0.001; n = 10, mean ± s.d. d, The spatial memory defect in ACSS2-knockdown mice manifests in a lowered discrimination index (% DI = (t NL – t FL)/(t NL+ t FL)) compared to control mice (ΔDI = −29.5 ± 11.4, *P = 0.02; n = 10, mean ± s.d.). e, Training-induced expression of a cohort of immediate early genes (Extended Data Fig. 8h) is greatly attenuated in ACSS2-knockdown mice (n = 4 mice per group, 2 replicates for each condition, P < 0.0001, paired t-test, mean ± s.d.). f, Model for function of ACSS2 as a chromatin-bound coactivator to provide acetyl-CoA locally to promote histone acetylation and activity-induced upregulation of immediate early genes.