SMARCA3, a Chromatin-Remodeling Factor, Is Required for p11-Dependent Antidepressant Action

Abstract

SUMMARY p11, through unknown mechanisms, is required for behavioral and cellular responses to selective serotonin-reuptake inhibitors (SSRIs). Here we have identified SMARCA3, a chromatin-remodeling factor, as a novel target for the p11/annexin A2 heterotetrameric complex. Determination of the crystal structure indicates that SMARCA3 peptide binds to a hydrophobic pocket in the heterotetramer. Formation of this complex increases the DNA binding affinity of SMARCA3 and its localization to the nuclear matrix fraction. In the dentate gyrus, both p11 and SMARCA3 are highly enriched in hilar mossy cells and basket cells. In response to the SSRI, fluoxetine, the expression of p11 is induced in both cell types, and the amount of the ternary complex of p11/annexin A2/SMARCA3 is increased. SSRI-induced neurogenesis and behavioral responses are abolished by constitutive knockout of SMARCA3. Our studies indicate a central role for a chromatin-remodeling factor in the SSRI/p11 signaling pathway, and suggest a novel approach to the development of improved antidepressant therapies.

Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress

“…Similar to our observations in chronic stress, NUP62 transcript content in prefrontal cortex of major depressives is reduced to 82% of control levels in the absence of significant changes in other nucleoporins (13). Intriguingly, the therapeutic effect of selective serotonin reuptake inhibitors in treating depression has been shown recently to involve chromatin remodeling through p11/AnxA2 signaling to the SMARCA3 remodeling factor (45). It is an interesting possibility that the therapeutic action of antidepressive agents may involve correcting changes in chromatin organization that result from reductions in NUP62 content.…”

Treatment-resistant depression: are animal models of depression fit for purpose?

“…A final target related to serotoninergic neurotransmission is p11 (which recruits 5-HT1B receptors to the cell membrane) and its target SMARCA3. Ablation of p11 abolished the effects of chronic imipramine in the open field and induced increased thigmotaxis (suggesting heightened anxiety behaviour) (Svenningsson et al 2006), while ablation of SMARCA3 suppressed the effect of chronic escitalopram on stress-induced anhedonia (Oh et al 2013). However, ablation of SMARCA3 did not modify sucrose consumption after chronic stress (or the effects of acute escitalopram in the tail suspension test) (Oh et al 2013).…”

Fluoxetine: a case history of its discovery and preclinical development

“…Thus, chronic fluoxetine treatment is able to reverse some of these changes and interestingly, these miRNAs alterations are also reversed by the nonpharmacological electroconvulsive therapy [52]. Even more, other new mechanisms have been proposed for this antidepressant, for example a recent study involves a chromatinremodelling factor in the antidepressant effect of fluoxetine [53]. Overall, the mechanism of action of this compound could open an avenue for understanding.…”