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Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.

Dale E, Zhang H, Leiser SC, Xiao Y, Lu D, Yang CR, Plath N, Sanchez C - J. Psychopharmacol. (Oxford) (2014)

Bottom Line: Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism.In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures.Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Lundbeck Research USA, Paramus, NJ, USA EDAL@lundbeck.com.

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Related in: MedlinePlus

Serotonin (5-HT) increased frequency and amplitude of spontaneous inhibitory post-synaptic currents (sIPSCs), but not miniature inhibitory post-synaptic currents (mIPSCs), recorded from hippocampal CA1 pyramidal cells. (a1), (b1) Representative traces of sIPSCs (a1) and mIPSCs (b1) recorded from a CA1 pyramidal cell before and after local application of 5-HT (100 µM for 500 ms). mIPSCs were recorded in the presence of 1 µM tetrodotoxin (TTX). (a2), (a3) Serotonin (5-HT) transiently increased the frequency ((a2), ****p<0.001, **p=0.0078, *p=0.0361, one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test vs baseline) and amplitude ((a3), ****p<0.001, *p=0.0235, one-way ANOVA with Dunnett’s multiple comparisons test vs baseline) of sIPSCs. The largest increase was observed in the first 15 s after 5-HT application and the response to 5-HT was largely desensitized after 60 s. Bars represent the mean±standard error of the mean (SEM) of recordings from 10 cells. (b2), (b3) 5-HT had no effect on mIPSC frequency (b2) or amplitude (b3) (p>0.05, paired Student’s t-test). Bars represent the mean±SEM of 60 s recordings from four cells.
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fig1-0269881114543719: Serotonin (5-HT) increased frequency and amplitude of spontaneous inhibitory post-synaptic currents (sIPSCs), but not miniature inhibitory post-synaptic currents (mIPSCs), recorded from hippocampal CA1 pyramidal cells. (a1), (b1) Representative traces of sIPSCs (a1) and mIPSCs (b1) recorded from a CA1 pyramidal cell before and after local application of 5-HT (100 µM for 500 ms). mIPSCs were recorded in the presence of 1 µM tetrodotoxin (TTX). (a2), (a3) Serotonin (5-HT) transiently increased the frequency ((a2), ****p<0.001, **p=0.0078, *p=0.0361, one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test vs baseline) and amplitude ((a3), ****p<0.001, *p=0.0235, one-way ANOVA with Dunnett’s multiple comparisons test vs baseline) of sIPSCs. The largest increase was observed in the first 15 s after 5-HT application and the response to 5-HT was largely desensitized after 60 s. Bars represent the mean±standard error of the mean (SEM) of recordings from 10 cells. (b2), (b3) 5-HT had no effect on mIPSC frequency (b2) or amplitude (b3) (p>0.05, paired Student’s t-test). Bars represent the mean±SEM of 60 s recordings from four cells.

Mentions: Consistent with published results, local application of 5-HT significantly increased sIPSCs recorded from CA1 pyramidal cells (Figure 1(a1)). Approximately 85% of cells responded to 5-HT with a burst-like enhancement in sIPSC frequency and amplitude. Only those cells were included in the analysis of this study (n=24 cells). The effect of 5-HT was always transient and lasted for ~60 s (Figures 1(a1)–(a3)). Because of rapid desensitization, 5-HT was applied focally onto the surface of the slice via a fast speed perfusion system. Although fast desensitizing, 5-HT responses were repeatable after a 3–5 min washout (data not shown). Frequency and amplitude analyses for 60 s of recordings for 10 representative cells following 5-HT application are shown in Figures 1(a2) and 1(a3). Peak 5-HT response was observed within the first 15 s, during which sIPSC frequency and amplitude were increased by 301±34% and 261±26%, respectively (n=24 cells).


Vortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus.

Dale E, Zhang H, Leiser SC, Xiao Y, Lu D, Yang CR, Plath N, Sanchez C - J. Psychopharmacol. (Oxford) (2014)

Serotonin (5-HT) increased frequency and amplitude of spontaneous inhibitory post-synaptic currents (sIPSCs), but not miniature inhibitory post-synaptic currents (mIPSCs), recorded from hippocampal CA1 pyramidal cells. (a1), (b1) Representative traces of sIPSCs (a1) and mIPSCs (b1) recorded from a CA1 pyramidal cell before and after local application of 5-HT (100 µM for 500 ms). mIPSCs were recorded in the presence of 1 µM tetrodotoxin (TTX). (a2), (a3) Serotonin (5-HT) transiently increased the frequency ((a2), ****p<0.001, **p=0.0078, *p=0.0361, one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test vs baseline) and amplitude ((a3), ****p<0.001, *p=0.0235, one-way ANOVA with Dunnett’s multiple comparisons test vs baseline) of sIPSCs. The largest increase was observed in the first 15 s after 5-HT application and the response to 5-HT was largely desensitized after 60 s. Bars represent the mean±standard error of the mean (SEM) of recordings from 10 cells. (b2), (b3) 5-HT had no effect on mIPSC frequency (b2) or amplitude (b3) (p>0.05, paired Student’s t-test). Bars represent the mean±SEM of 60 s recordings from four cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2 - License 3
Show All Figures
getmorefigures.php?uid=PMC4230848&req=5

fig1-0269881114543719: Serotonin (5-HT) increased frequency and amplitude of spontaneous inhibitory post-synaptic currents (sIPSCs), but not miniature inhibitory post-synaptic currents (mIPSCs), recorded from hippocampal CA1 pyramidal cells. (a1), (b1) Representative traces of sIPSCs (a1) and mIPSCs (b1) recorded from a CA1 pyramidal cell before and after local application of 5-HT (100 µM for 500 ms). mIPSCs were recorded in the presence of 1 µM tetrodotoxin (TTX). (a2), (a3) Serotonin (5-HT) transiently increased the frequency ((a2), ****p<0.001, **p=0.0078, *p=0.0361, one-way analysis of variance (ANOVA) with Dunnett’s multiple comparisons test vs baseline) and amplitude ((a3), ****p<0.001, *p=0.0235, one-way ANOVA with Dunnett’s multiple comparisons test vs baseline) of sIPSCs. The largest increase was observed in the first 15 s after 5-HT application and the response to 5-HT was largely desensitized after 60 s. Bars represent the mean±standard error of the mean (SEM) of recordings from 10 cells. (b2), (b3) 5-HT had no effect on mIPSC frequency (b2) or amplitude (b3) (p>0.05, paired Student’s t-test). Bars represent the mean±SEM of 60 s recordings from four cells.
Mentions: Consistent with published results, local application of 5-HT significantly increased sIPSCs recorded from CA1 pyramidal cells (Figure 1(a1)). Approximately 85% of cells responded to 5-HT with a burst-like enhancement in sIPSC frequency and amplitude. Only those cells were included in the analysis of this study (n=24 cells). The effect of 5-HT was always transient and lasted for ~60 s (Figures 1(a1)–(a3)). Because of rapid desensitization, 5-HT was applied focally onto the surface of the slice via a fast speed perfusion system. Although fast desensitizing, 5-HT responses were repeatable after a 3–5 min washout (data not shown). Frequency and amplitude analyses for 60 s of recordings for 10 representative cells following 5-HT application are shown in Figures 1(a2) and 1(a3). Peak 5-HT response was observed within the first 15 s, during which sIPSC frequency and amplitude were increased by 301±34% and 261±26%, respectively (n=24 cells).

Bottom Line: Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism.In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures.Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus.

View Article: PubMed Central - PubMed

Affiliation: Lundbeck Research USA, Paramus, NJ, USA EDAL@lundbeck.com.

Show MeSH
Related in: MedlinePlus