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<img class="aligncenter" src="https://scx1.b-cdn.net/csz/news/800a/2023/study-explains-how-ant.jpg"
alt="Study explains how antidepressant increases brain plasticity"
title="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)&nbsp;mice. b Scheme of the fear-conditioning paradigm. Mice were conditioned by pairing a tone and an electric shock in context A&nbsp;(c), and then&nbsp;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), can it take 8 weeks for lexapro to work 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 &lt; 0.0001). However, PV-TrkB hCKO mice showed significantly higher freezing compared to wild-type mice (Genotype, F (1, 270) = 4.049, P &lt; 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 &lt; 0.0001) and an effect of fluoxetine treatment on both days (Treatment, Ext1, F (1, 336) = 34.34, P &lt; 0.0001, Sidak’s post hoc test for trial 5, P = 0.0034; Ext2, F (1, 336) = 39.68, P &lt; 0.0001, Sidak’s test for trial 1, P = 0.0061; trial 6, P = 0.0025; **P &lt; 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 &lt; 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 &lt; 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 &lt; 0.05; **P &lt; 0.01. Credit: Neuropsychopharmacology (2023). DOI: 10.1038/s41386-023-01562-y” width=”800″ height=”530″>

A recent study, published in Neuropsychopharmacology, conducted by researchers from the University of Helsinki and the University of Eastern Finland, sheds light on the mechanisms of neural plasticity induced by the antidepressant fluoxetine.

Previous research by the same team showed that chronic treatment with antidepressants increased neural plasticity through direct binding to neurotrophic receptor TrkB, but the mechanism of relevant neural circuits remained unknown.

In the current study, the researchers conducted a classical fear conditioning paradigm with mice and discovered that fluoxetine facilitated the erasure of learned fear responses, as well as decreased the spontaneous reactivation of these responses. Additionally, the mice exhibited faster learning of spatial patterns in pairwise tests when treated with fluoxetine, particularly when the task was reversed.

However, the effects were diminished or absent in mice with lower TrkB receptor expression in their PV+ interneurons, an important class of GABAergic inhibitory neurons, responsible for regulating the activity of excitatory neurons and playing a crucial role in various functions, such as cognitive processes and memory.

The researchers also analyzed gene expression specifically in PV+ interneurons following fluoxetine treatment. They found changes related to GABAergic synapses, axon guidance, and enzymes involved in the formation of perineuronal net (PNN), an extracellular matrix surrounding PV+ interneurons, which plays a role in regulating neuronal plasticity.

Moreover, they observed a decrease in the number of PV+ interneurons with PNN and a reduction in the intensity of PNN following fluoxetine treatment, indicating enhanced plasticity of PV+ interneurons. However, this effect was attenuated in mice with lower TrkB receptor expression in PV+ interneurons.

The results of the study suggest that the TrkB receptor in PV+ interneurons is primarily responsible for the increased reversal learning observed with fluoxetine treatment. These findings may offer new perspectives for the development for psychiatric diseases and pave the way for new medications targeting brain plasticity via PV+ interneurons.

More information:
Elias Jetsonen et al, Activation of TrkB in Parvalbumin interneurons is required for the promotion of reversal learning in spatial and fear memory by antidepressants, Neuropsychopharmacology (2023). DOI: 10.1038/s41386-023-01562-y

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