Selective modulation of Ca2+ influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus

doi:10.1016/j.brainres.2005.01.001

Brain Research

Volume 1037, Issues 1–2, 10 March 2005, Pages 187-193

https://doi.org/10.1016/j.brainres.2005.01.001 Get rights and content

Abstract

Both long-term potentiation (LTP) and long-term depression (LTD) can be induced in the Schaffer collateral-CA1 synapse of the hippocampus either by repetitive stimulation of afferent fibres with the frequency of the stimulation determining the polarity of the response or by associative pairing of pre- and postsynaptic activity. An increase in postsynaptic intracellular Ca²⁺ concentration is an important signal for the induction of long-term synaptic plasticity. In patch-clamp experiments on hippocampal brain slices, we tested the modulation of different forms of synaptic plasticity by the neurotransmitter serotonin (5-HT) which is known to inhibit high-voltage activated Ca²⁺ channels. 1 μM of 5-HT inhibited homosynaptic LTD induced by low frequency stimulation. This effect of 5-HT could be blocked by the selective 5-HT_1A antagonist WAY 100635. Low frequency-induced LTD is both dependent on Ca²⁺ influx through NMDA receptors and high-voltage activated Ca²⁺ channels. It was blocked by the NMDA-receptor antagonist D-AP5 and by the N-type Ca²⁺ channel antagonist ω-conotoxin GIVA. Tetanus induced LTP was not affected by low concentrations of 5-HT, whereas depotentiation of LTP by asynchronous pairing of EPSPs and postsynaptic action potentials was completely abolished with 5-HT in the bath solution. We conclude that those forms of plasticity which depend on Ca²⁺ influx via high-voltage activated Ca²⁺ channels are subject to modulation by 5-HT. This might be a relevant mechanism by which 5-HT modifies basic network properties in the brain.

Introduction

The serotonergic pathway from the raphe nuclei widely projects to most brain regions; 5-HT receptors are abundant on dendritic and somatic structures of pre- and postsynaptic neurons [15], [41]. 5-HT is important in the regulation of a variety of sensory, motor, and cortical functions and has been implicated in the regulation of memory and cortical development as well as in the pathophysiology of several disease states, including depression, anxiety, and schizophrenia [2], [11], [18]. On a cellular level, 5-HT has been reported to modulate neuronal firing properties, neurogenesis in the adult hippocampus as well as the induction of different forms of synaptic plasticity [1], [34].

Long-term synaptic plasticity (long-term potentiation/LTP, long-term depression/LTD) determines basic properties of signal processing in neural networks. It is regarded as the molecular basis of learning and memory [3]. Initially shown in the hippocampus [4], an activity-driven modification of synaptic strength has been identified in many regions of the central nervous system. Correspondingly, physiological consequences of long-term synaptic plasticity in different brain regions have been extended from classical spatial learning paradigms to fear conditioning, stress-related behavior, and affective regulation [19], [23], [31], [42].

Both LTP and LTD can be induced either by repetitive stimulation of afferent fibers or by associative pairing of pre- and postsynaptic activity. Using homosynaptic induction protocols, a high-frequency tetanus of afferent fibers induces LTP, whereas prolonged stimulation at moderate frequencies results in LTD [7]. Different groups have investigated the modulation of different homosynaptic forms of long-term synaptic plasticity by 5-HT. Bliss et al. [5] showed a reduction of LTP in the dentate gyrus in 5-HT-depleted, anaesthetized rats. In the hippocampus, different serotonergic receptors have been examined: 5-HT_1A and 5-HT_2A had an inhibiting, 5-HT₄ a facilitating effect, whereas 5-HT_2C was without effect on Schaffer collateral to CA1 LTP [16], [20], [22], [39], [40]. Stäubli reported a disinhibition of pyramidal cells and an enhancement of LTP in freely moving rats upon pharmacological block of 5-HT₃ receptors in inhibitory interneurons [32], [38]. Huang et al. [14] showed that the 5-HT_1A receptor agonist buspirone, applied shortly after induction of tetanus-induced LTP, caused a depotentiation of LTP. There is less data on serotonergic regulation of homosynaptic LTD: high concentrations of 5-HT inhibited LTD predominantly in interneurons in the basolateral amygdala [30], whereas LTD in rat deep dorsal horn neurons was increased [12]. In freely moving rats, activation of the 5-HT₄-receptor inhibited depotentiation of LTP [17].

In this electrophysiological study, we examined the modulation of different forms of synaptic plasticity and its mechanisms by 5-HT.

Section snippets

Slice preparation

Transverse 300-μm-thick slices were cut from the hippocampus of 11- to 22-day-old Wistar rats with a vibratome (DTK-1000, Dosaka, Japan). For most experiments 14- to 18-day-old animals were used. The animals were killed by decapitation, in accordance with national and institutional guidelines. Slices were kept at 35 °C for 30 min after slicing and then at room temperature in physiological extracellular saline containing (in mM): 125 NaCl, 25 NaHCO₃, 25 glucose, 2.5 KCl, 1.25 NaH₂PO₄, 2 CaCl₂,

Results

Homosynaptic LTD was induced by low-frequency stimulation (LFS) of presynaptic fibers. A stimulation frequency below 10 Hz has been shown to induce LTD of the CA3–CA1 synapse [7]. We used a 5-Hz tetanus which was applied for 3 min (900 EPSPs). The reduction of the EPSP amplitude was measured. The low frequency stimulation caused no spiking of the postsynaptic cell; however, a slight depolarization of the membrane potential to −62 mV was necessary to achieve LTD. This protocol induced a

Discussion

In our study, we have shown that LTD induced by low-frequency stimulation depends both on Ca²⁺ influx through NMDA receptors and high-voltage activated Ca²⁺ channels. This makes LFS-LTD accessible to serotonergic modulation whereas tetanus-induced LTP can only be blocked by excessively high concentrations of 5-HT.

Acknowledgment

C.N. was supported by a grant from the Deutsche Forschungsgemeinschaft No 370/3.

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Research reportSelective modulation of Ca2+ influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus

Abstract

Introduction

Section snippets

Slice preparation

Results

Discussion

Acknowledgment

Prog. Brain Res.

Trends Neurol. Sci.

Brain Res.

Trend Neurol. Sci.

Neuron

Pharmacol. Biochem. Behav.

Neuron

Brain Res.

Neuron

Neuroscience

Brain Res.

Brain Res.

Pharmacologically distinct actions of serotonin on single pyramidal neurons of the rat hippocampus recorded in vitro

J. Physiol.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path

J. Physiol.

Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines

J. Physiol.

Postsynaptic induction and presynaptic expression of hippocampal long-term depression

Science

Homosynaptic long term depression in area CA1 of the hippocampus and effects of NMDA receptor blockade

Proc. Natl. Acad. Sci. U. S. A.

Propagation of activity-dependent synaptic depression in simple neural networks

Nature

Serotonin modulates N- and P-type calcium currents in neocortical pyramidal neurons via a membrane-delimited pathway

J. Neurophysiol.

The neurochemistry of mood disorders: clinical studies

Research report
Selective modulation of Ca²⁺ influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus