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. 2019 Aug 2;10:3469. doi: 10.1038/s41467-019-11409-0

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — Acute chemical-genetic control of nuclear repression with destabilized HDAC4. a Schematics of stabilization of DD-nHDAC4 protein with TMP and Rosa26 allele for Cre-dependent expression of DD-nHDAC4 form the CAG promoter (R26^{floxStop-DD-nHDAC4}). See also Supplementary Fig. 8a. b–k DD-nHDAC4 was introduced into excitatory forebrain neurons by crossing R26^{floxStop-DD-nHDAC4} mice with Camk2α^Cre. TMP-lactate (300 μg/gm body weight) or control vehicle solutions were administered via intraperitoneal injections. b Brains were isolated at p60 3 h after drug delivery. Cortical and cerebellar protein extracts were probed by immunoblotting with antibodies against FLAG or HDAC4. c, d Time course of DD-nHDAC4 stabilization in the cortex. Immunoblot of samples isolated at different intervals after TMP injection (c) and quantifications of DD-nHDAC4 levels (d, r.u.) are shown. n = 3-4 mice/time point. e Images of DD-nHDAC4 immunofluorescence in CA3sp of vehicle and TMP-treated R26^{floxStop-DD-nHDAC4}/Camk2α^Cre mice (3 h post injection). See also Supplementary Fig. 8b. f–h Stabilized DD-nHDAC4 represses ERGs. R26^{floxStop-DD-nHDAC4}/Camk2α^Cre mutants were given single doses of vehicle or TMP. Animals were maintained in home cages (HC) or subjected to CFC (3 h post-injection). After 1.5 h, brains were sectioned and labeled with antibodies against FLAG, Egr1, or Fos. Panels show images of the CA3 (f) and averaged densities of Erg1/Fos-positive cells in this area (g, h). See also Supplementary Fig. 8c. i–k Effects of TMP-inducible nuclear repression on associative memory. p60 R26^{floxStop-DD-nHDAC4}/Camk2α^Cre and Cre-negative R26^{floxStop-DD-nHDAC4} mice were treated with vehicle or TMP prior to CFC or prior to contextual memory retrieval, as depicted in i. j Freezing of animals that were given drugs 3 h before learning. Control + vehicle: n = 12; Control + TMP: n = 9; DD-nHDAC4 + vehicle: n = 12; DD-nHDAC4 + TMP: n = 12. k Freezing of animals that were given drugs 3 h before memory recall. Control + vehicle: n = 11; Control + TMP: n = 11; DD-nHDAC4 + vehicle: n = 19; DD-nHDAC4 + TMP: n = 9. All quantifications are represented as Mean ± SEM. *p < 0.05 (t-test and ANOVA). Actual p-values are indicated in each graph (vertical for t-test and horizontal for ANOVA)