5-Hydroxytryptamine Induces a Protein Kinase A/Mitogen-Activated Protein Kinase-Mediated and Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation in the Amygdala

Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

Section: Discussionmentioning

confidence: 99%

Chronic Enhancement of Serotonin Facilitates Excitatory Transcranial Direct Current Stimulation-Induced Neuroplasticity

Kuo

Paulus

Batsikadze

et al. 2015

“…Student's t-tests revealed no significant differences between conditions (p40.05). Impact of serotonin on neuroplasticity G Batsikadze et al animal studies have shown that serotonin can enhance LTP (Huang and Kandel, 2007;Kojic et al, 1997;Machacek et al, 2001;Mori et al, 2001;Ohashi et al, 2002;Park et al, 2012), block the stress-caused inhibition of LTP (Ryan et al, 2008) or block LTD . Activation of 5-HT receptors was furthermore shown to reverse LTD induction or convert it into LTP (Costa et al, 2012;Kemp and Manahan-Vaughan, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…However, activation of serotoninergic receptors also had opposing results on plasticity in other studies. Some studies have shown negative or no effect of serotonin on LTP induction (Edagawa et al, 1998;Huang and Kandel, 2007;Kojima et al, 2003;Normann et al, 2007;Sanberg et al, 2006), which can be explained by activation of different serotoninergic receptor subtypes, stage of brain development or dosage and frequency of application of 5-HT agonists or antagonists Park et al, 2012;Staubli and Otaky, 1994). To explore the reasons of such opposing results, future studies should address specific serotoninergic receptor subtypes, using different 5-HTreceptor agonist or antagonist drugs.…”

Section: Discussionmentioning

confidence: 99%

“…One important foundation for these effects might be its impact on neuroplasticity. Activation of serotoninergic subreceptors is shown to affect long-term potentiation (LTP) or longterm depression (LTD) in animal slice preparations, depending on subreceptor type, location and frequency of application (Huang and Kandel, 2007;Kojic et al, 1997;Mori et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Serotonin on Paired Associative Stimulation-Induced Plasticity in the Human Motor Cortex

Batsikadze

Paulus

Kuo

et al. 2013

Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo-controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory-and excitability-diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation-elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke.

“…Thus, although task-or speciesrelated factors may contribute in the present spine growth pattern, the observation that spine density was increased at all dendritic loci in trained mice injected with SL65.0155 suggests that activation of 5-HT 4 Rs globally enhances connectivity and excitatory neurotransmission in learningactivated hippocampal circuits. Additional support for a role of 5-HT 4 Rs in the remodeling of experience-induced synaptic contacts comes from data showing that induction of late facilitation of synaptic transmission (L-LTP) in amygdala slices by local applications of the 5-HT 4 agonist RS67333 requires both protein synthesis and cytoskeletal rearrangements (Huang and Kandel, 2007). Thus, 5-HT 4 Rsmediated L-LTP elicits neuronal rewiring in the amygdala presumably favoring the storage of emotional memories in amygdalar circuits.…”

Section: Discussionmentioning

confidence: 99%

The Promnesic Effect of G-protein-Coupled 5-HT4 Receptors Activation Is Mediated by a Potentiation of Learning-Induced Spine Growth in the Mouse Hippocampus

Restivo

Roman

Dumuis

et al. 2007

Pharmacological modulation of synaptic efficacy is a prominent target in the identification of promnesic compounds. Here, we report that pretraining administration of the serotonin 5-HT 4 receptors (5-HT 4 Rs) partial agonist SL65.0155 enhances simultaneous olfactory discrimination performance and potentiates learning-induced dendritic spine growth in the mouse hippocampus. SL65.0155 does not affect spine density in the pseudo-trained mice and, by itself, does not promote spine growth. Injecting the 5-HT 4 antagonist RS39604 prior to SL65.0155 prevents both the increase in performance and the additional formation of spines, thus confirming the 5-HT 4 Rs specificity of the observed effects. These findings provide evidence that 5-HT 4 Rs stimulation selectively increases experience-dependent structural plasticity in learning-activated hippocampal circuits.