Actions of 5-HT on human neocortical neurones in vitro

Newberry, Nigel R.; Footitt, David; Papanastassiou, Vakis; Reynolds, David J.

doi:10.1016/s0006-8993(99)01540-1

Cited by 31 publications

(23 citation statements)

References 29 publications

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“…Apart from axon terminals, the proximal part of the axon initial segment of pyramidal cells reportedly expressing 5HT-1A receptors (DeFelipe et al, 2001) could also contribute to serotonergic effects, possibly by gating the propagation of action potentials between the somatodendritic and axonal compartment through local hyperpolarization (Newberry et al, 1999). In line with a previous study (Newberry et al, 1999) a minor fraction of pyramidal cells were hyperpolarized by 5-HT.…”

Section: Discussionsupporting

confidence: 82%

“…5HT-1A and 2A receptors are considered to have opposite effects on the excitability of postsynaptic neurons (Newberry et al, 1999;Andrade, 2011). Although 5HT-2A receptors have a relatively low affinity for serotonin (Barnes and Sharp, 1999), suppression of glutamate release with 5-HT mediated by both of these two receptor types was shown in the cerebellum (Maura et al, 1988) and 5-HT 1-A-mediated presynaptic decrease of glutamatergic transmission was reported in the entorhinal cortex of rat (Schmitz et al, 1998a,b) in addition to our experiments.…”

Section: Discussionmentioning

confidence: 99%

“…2C,G) showing that GABAergic axon terminals were not modulated by 5-HT. Apart from GABAergic components of the microcircuit, serotonergic effects might target the function of pyramidal cells Boddeke, 1993, 1996;Schmitz et al, 1998a,b;Newberry et al, 1999). First we investigated the effects of 100 nM 5-HT on the resting membrane potential of pyramidal cells.…”

Section: Network Mechanisms Underlying Serotonergic Suppression Of Simentioning

confidence: 99%

“…Humans (Harmer et al, 2003;Schmitt et al, 2006) and animals (Clarke et al, 2004;Brigman et al, 2010) display altered cognitive performance after having their central 5-HT level experimentally manipulated. With limited studies performed on human pyramidal cells (McCormick and Williamson, 1989;Newberry et al, 1999), our current knowledge about synaptic mechanisms of 5-HT in the cortex is based on non-human in vitro experiments in which micromolar concentrations of 5-HT were applied (Andrade and Nicoll, 1987;Aghajanian and Marek, 1997;Schmitz et al, 1998b;Ciranna, 2006;Zhong et al, 2008). However, single spikes in serotonergic axons produce extrasynaptic concentrations of 50 -100 nM and the maximal concentration achieved by electrical stimulation is 500 -800 nM (Bunin and Wightman, 1998) and few studies tested the effect of nanomolar serotonin concentrations (Boeijinga and Boddeke, 1993;Winterer et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

et al. 2012

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Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Network Mechanisms Underlying Serotonergic Suppression Of Simentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

et al. 2012

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“…Furthermore, the activity of glutamatergic neurons in the hippocampus and neocortex is modulated by cholinergic systems, which have facilitatory effects mediated via muscarinic receptors (Cole and Nicoll, 1984;Segal, 1982), and serotonergic systems, which have inhibitory effects partly mediated via 5-HT 1A receptors (Beck et al, 1992;Davies et al, 1987;Newberry et al, 1999;Pugliese et al, 1998). Thus, 5-HT 1A receptor agonists such as 8-hydroxy-2-(di-n-propyloamino)tetralin hydrobromide (8-OH-DPAT) have been found to cause a hyperpolarization of limbic (hippocampus and entorhinal cortex) (Grunschlag et al, 1997;Sprouse and Aghajanian, 1988;Tada et al, 1999) and neocortical pyramidal cells (Hajos et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

Misane

Ögren

2003

Neuropsychopharmacol

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Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT 1A receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1) a functional 5-HT 1A receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2) the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT 1A receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease.

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Pyramidal cell axons show a local specialization for GABA and 5‐HT inputs in monkey and human cerebral cortex

DeFelipe

Arellano

Gómez³

et al. 2001

J of Comparative Neurology

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Various mechanisms are thought to control excitation of pyramidal cells of the cerebral cortex. With immunocytochemical methods, we found that the proximal portions of numerous pyramidal cell axons (Pyr-axons) in the human and monkey neocortex are immunoreactive for the serotonin (5-HT) receptor 5-HT-(1A). With double-labeling experiments and confocal laser microscopy, we found that most (93.4%) of the 5-HT(1A)-immunoreactive Pyr-axons present in layers II and III were innervated by parvalbumin-immunoreactive chandelier cell axon terminals. In addition, Pyr-axons were compartmentalized: 5-HT-(1A) receptors were found proximal to inputs from chandelier cells. Although we found close appositions between GABAergic chandelier cell axon terminals and Pyr-axons, suggesting synaptic connections, we did not observe 5-HT-immunoreactive fibers in close proximity to the Pyr-axons. These results suggested that Pyr-axons are under the influence of 5-HT in a paracrine manner (via 5-HT-(1A) receptors) and, more distally, are under the influence of gamma-aminobutyric acid (GABA) in a synaptic manner (through the axons of chandelier cells). The local axonal specialization might represent a powerful inhibitory mechanism by which the responses of large populations of pyramidal cells can be globally controlled by subcortical serotonin afferents, in addition to local inputs from GABAergic interneurons.

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Actions of 5-HT on human neocortical neurones in vitro

Cited by 31 publications

References 29 publications

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

Selective 5-HT1A Antagonists WAY 100635 and NAD-299 Attenuate the Impairment of Passive Avoidance Caused by Scopolamine in the Rat

Pyramidal cell axons show a local specialization for GABA and 5‐HT inputs in monkey and human cerebral cortex

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