Fig 1: Early, chronic fluoxetine treatment normalizes HDAC4- and MEF2A-dependent transcription in adult Arid1b+/– mice.a Genes that strongly contribute to positive enrichment of Arid1b-Flx/Veh transcripts in the FMRP target gene set (Fig. 6c). b The working hypothesis in the left panel suggests that a decrease in the total levels of HDAC4 in Arid1b+/– mice may lead to decreases in the nuclear levels of HDAC4, insufficient repression of the transcription factor MEF2A (as shown by insufficient phosphorylation), and resulting excessive expression of SynGAP1/Arc (negative synaptic regulators) and suppression of excitatory synapses. The right panel suggests that these changes in Arid1b+/– mice are reversed by early postnatal chronic fluoxetine treatment. c Total and nuclear (P1 fraction) levels of HDAC4 protein in adult (P120) WT and Arid1b+/– mice treated early (P3–21) with vehicle or fluoxetine. (n = 3 [WT-Veh], 3 [WT-Flx], 3 [HT-Veh], and 3 [HT-Flx], two-way ANOVA with Tukey’s test and two-tailed Student’s t-test; the positive drug effect in the ANOVA led us to attempt two-tailed Student’s t-tests for multiple comparisons (indicated by # signs), [Whole-brain, WT-Veh vs HT-Veh: p = 0.0285, WT-Veh vs WT-Flx: p = 0.9925, WT-Veh vs HT-Flx: p = 0.9978, HT-Veh vs WT-Flx: p = 0.0416, HT-Veh vs HT-Flx: p = 0.0366, WT-Flx vs HT-Flx: p = 0.9997], [P1 fraction, WT-Veh vs HT-Veh: p = 0.0173, WT-Veh vs WT-Flx: p = 0.1209, WT-Veh vs HT-Flx: p = 0.3610, HT-Veh vs WT-Flx: p = 0.0038, HT-Veh vs HT-Flx: p = 0.0375, WT-Flx vs HT-Flx: p = 0.8347]). d Total and S408-phosphorylated levels of MEF2A in adult (P120) WT and Arid1b+/– mice treated early (P3–21) with vehicle or fluoxetine. (n = 3 [WT-Veh], 3 [WT-Flx], 3 [HT-Veh], and 3 [HT-Flx], two-way ANOVA and two-tailed Student’s t-test, [pMEF2A, WT-Veh vs HT-Veh: p = 0.0199, WT-Veh vs WT-Flx: p = 0.8571, WT-Veh vs HT-Flx: p = 0.9018, HT-Veh vs WT-Flx: p = 0.0093, HT-Veh vs HT-Flx: p = 0.0035, WT-Flx vs HT-Flx: p = 0.7051]). e Total levels of SynGAP1 and Arc proteins in adult (P120) WT and Arid1b+/– mice treated early with (P3–21) vehicle or fluoxetine. (n = 3 [WT-Veh], 3 [WT-Flx], 3 [HT-Veh], and 3 [HT-Flx], two-way ANOVA with Tukey’s test, [SynGAP, WT-Veh vs HT-Veh: p = 0.0605, WT-Veh vs WT-Flx: p > 0.9999, WT-Veh vs HT-Flx: p = 0.9007, HT-Veh vs WT-Flx: p = 0.0631, HT-Veh vs HT-Flx: p = 0.0233, WT-Flx vs HT-Flx: p = 0.8893], [Arc, WT-Veh vs HT-Veh: p = 0.0118, WT-Veh vs WT-Flx: p = 0.7801, WT-Veh vs HT-Flx: p = 0.9961, HT-Veh vs WT-Flx: p = 0.0432, HT-Veh vs HT-Flx: p = 0.0089, WT-Flx vs HT-Flx: p = 0.6623]). Graphical data are presented as means ± SEM (*p < 0.05, **p < 0.01, ***p < 0.001, ns, not significant). Source data are provided as a Source Data file.
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