Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.

In drug discovery, structural modifications over the lead molecule are often crucial for the development of a drug. Herein, we reported the first in vivo bioisosteric effect of phosphinolactone function in relation to the lactol group constituting the bioactive molecule: Hydroxybupropion. The preparation of phosphinolactone analogues and their antidepressant evaluation towards forced swimming test in mice showed that biological activity was regained and even strengthen.

Background and purpose: Tetrahydro‐N, N‐dimethyl‐5, 5‐diphenyl‐3‐furanmethanamine hydrochloride (ANAVEX1‐41) is a potent muscarinic and sigma₁(σ₁) receptor ligand. Theσ₁receptor modulates glutamatergic and cholinergic responses in the forebrain and selective agonists are potent anti‐amnesic and antidepressant drugs. We have here analysed theσ₁component in the behavioural effects of ANAVEX1‐41.Experimental approach: Binding of ANAVEX1‐41 to muscarinic andσ₁receptors were measured using cell membranes. Behavioural effects of ANAVEX1‐41 were tested in mice using memory (spontaneous alternation, passive avoidance, water‐maze) and antidepressant‐like activity (forced swimming) procedures.Key results: In vitro, ANAVEX1‐41 was a potent muscarinic (M₁>M₃, M₄>M₂with K_iranging from 18 to 114 nM) and selectiveσ₁ligand (σ₁, K_i=44 nM;σ₂, K_i=4 μM). In mice, ANAVEX1‐41 failed to affect learning when injected alone (0.03–1 mg kg⁻¹), but attenuated scopolamine‐induced amnesia with a bell‐shaped dose response (maximum at 0.1 mg kg⁻¹). Theσ₁antagonist BD1047 blocked the anti‐amnesic effect of ANAVEX1‐41 on both short‐ and long‐term memories. Pretreatment with aσ₁receptor‐directed antisense oligodeoxynucleotide prevented effects of ANAVEX1‐41 only in the passive avoidance procedure, measuring long‐term memory. ANAVEX1‐41 reduced behavioural despair at 30 and 60 mg kg⁻¹, without involving theσ₁receptor, as it was not blocked by BD1047 or the antisense oligodeoxynucleotide.Conclusions and implications: ANAVEX1‐41 is a potent anti‐amnesic drug, acting through muscarinic andσ₁receptors. The latter component may be involved in the enhancing effects of the drug on long‐term memory processes.British Journal of Pharmacology(2007)152, 267–279; doi:10.1038/sj.bjp.0707386