Fig. 1: Fluoxetine treatment promotes contextual and cued fear erasure which depends on TrkB expression in PV interneurons.

a Mating strategy to obtain wild-type and PV-specific heterozygous TrkB knockout (PV-TrkB hCKO) mice. b Scheme of the fear-conditioning paradigm. Mice were conditioned by pairing a tone and an electric shock in context A (c), and then one group was treated with fluoxetine (24 mg/kg/day). After 2 weeks, mice were subjected to 2 days of fear extinction training: day 1 (Ext1), day 2 (Ext2) wt (d), PV-TrkB hCKO (e). After 1 week, mice were tested for spontaneous recovery (SR) in context B (g, h) and fear renewal (FR) in context A (i, j). c Freezing was similarly increased during the conditioning/acquisition phase in both WT and hCKO mice and both genotypes reached a similar level of acquisition (two-way ANOVA, Conditioning, F (4, 270) = 21.94, P < 0.0001). However, PV-TrkB hCKO mice showed significantly higher freezing compared to wild-type mice (Genotype, F (1, 270) = 4.049, P < 0.0452; Sidak’s post hoc, wild-type vs PV-TrkB hCKO in Trial 3, P = 0.0037). d In wild-type mice, fear extinction trials significantly reduced freezing in both Ext1 (F (11, 336) = 1.988, P = 0.0288) and Ext2 (F (11, 336) = 9.624, P < 0.0001) and an effect of fluoxetine treatment on both days (Treatment, Ext1, F (1, 336) = 34.34, P < 0.0001, Sidak’s post hoc test for trial 5, P = 0.0034; Ext2, F (1, 336) = 39.68, P < 0.0001, Sidak’s test for trial 1, P = 0.0061; trial 6, P = 0.0025; **P < 0.01). e In PV-TrkB hCKO mice, extinction training significantly reduced the freezing in all PV-TrkB-hCKO mice only on day 2 (Ext1, trials, F (11, 288) = 0.8743, P = 0.5660; Ext2, trials, F (11, 288) = 0.8726, P < 0.0001) but fluoxetine treatment failed to significantly influence extinction (two-way ANOVA, treatment, Ext1, F (11, 288) = 3.866, P = 0.0502; Ext2, F (1, 288) = 3.776, P = 0.0530). f The effect of fluoxetine (delta: freezing in control (%) – fluoxetine (%)) between wild-type and PV-TrkB hCKO mice on each session in 2 days. The effect of fluoxetine on extinction was significantly more pronounced in wild-type than in PV-TrkB hCKO mice on both Ext1 (t-test, F = 1.616, DFn = 11, Dfd = 11, P = 0.0071) and Ext2 (t-test, F = 1.887, DFn = 11, Dfd = 11, P = 0.0108). g In SR, fluoxetine treatment significantly decreased freezing throughout sessions in wild-type mice (two-way ANOVA, Treatment, F (1, 112) = 14.05, P = 0.0003; Sidak’s post hoc test “water-treated vs Fluoxetine-treated” Trial 1, P = 0.0387) but not in PV-TrkB hCKO mice (Treatment, F (1, 96) = 1.876, P = 0.1739, Sidak’s post hoc test “water-treated vs Fluoxetine-treated” Trial 1, P = 0.9822). h Fluoxetine treatment significantly reduced spontaneous recovery in the first session of SR in the WT mice (Treatment, F (1, 52) = 4.585, P = 0.0370; Sidak’s post hoc test “water-treated vs Fluoxetine-treated” for wild-type P = 0.0229) but not in PV-TrkB hCKO mice (Sidak’s post hoc test “water-treated vs Fluoxetine-treated” for PV-TrkB hCKO P = 0.8618). i Freezing was reduced in repeated sessions after fear renewal by fluoxetine treatment in both wt (Treatment, F (1, 112) = 14.56, P = 0.0002; Sidak’s post hoc test “water-treated vs Fluoxetine-treated” Trial 1, P = 0.0159) and PV-TrkB hCKO mice (Treatment, F (1, 96) = 16.61, P < 0.0001; Sidak’s post hoc test “water-treated vs Fluoxetine-treated” Trial 1, P = 0.7996, Trial 2, P = 0.0195, Trial 3, P = 0.0243). j Fluoxetine attenuated fear renewal in the first session in wild-type (Treatment, F (1, 52) = 7.465, P = 0.0086; Sidak’s post hoc test “water-treated vs Fluoxetine-treated” P = 0.0122) but not PV-TrkB hCKO mice (Sidak’s post hoc test “water-treated vs Fluoxetine-treated” P = 0.4948). Error bars designate SEM. *P < 0.05; **P < 0.01.