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Sustained Activation of Postsynaptic 5-HT2A Receptors Gates Plasticity at Prefrontal Cortex Synapses.

Coralie Berthoux, Alexander Barre, Joël Bockaert, Philippe Marin, Carine Bécamel

Cerebral Cortex April 1, 2019 DOI: 10.1093/cercor/bhy064 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Basic science study using mouse brain slices (ex vivo electrophysiology) Peer reviewed
Population Mouse prefrontal cortex slices, including slices from 5-HT2A receptor-deficient mice
Interventions Serotonin 2 5-dimethoxy-4-iodoamphetamine (DOI)
Duration 20-minute exposure
Topics Serotonin
Keywords Layer i/v synapses Long-term depression Prefrontal cortex
Key points Serotonin or the 5-HT2A agonist DOI produced long-lasting depression of AMPA excitatory postsynaptic currents in layer V pyramidal neurons, an effect that required the 5-HT2A receptor and occluded electrically induced LTD. The authors argue this represents LTD gating by a G protein-coupled receptor that might cause imbalanced synaptic plasticity and memory impairment after nonphysiological serotonin elevation.

Abstract

The prefrontal cortex (PFC) plays a key role in many high-level cognitive processes. It is densely innervated by serotonergic neurons originating from the dorsal and median raphe nuclei, which profoundly influence PFC activity. Among the 5-HT receptors abundantly expressed in PFC, 5-HT2A receptors located in dendrites of layer V pyramidal neurons control neuronal excitability and mediate the psychotropic effects of psychedelic hallucinogens, but their impact on glutamatergic transmission and synaptic plasticity remains poorly characterized. Here, we show that a 20-min exposure of mouse PFC slices to serotonin or the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) produces a long-lasting depression of evoked AMPA excitatory postsynaptic currents in layer V pyramidal neurons. DOI-elicited long-term depression (LTD) of synaptic transmission is absent in slices from 5-HT2A receptor-deficient mice, is rescued by viral expression of 5-HT2A receptor in pyramidal neurons and occludes electrically induced long-term depression. Furthermore, 5-HT2A receptor activation promotes phosphorylation of GluA2 AMPA receptor subunit at Ser880 and AMPA receptor internalization, indicating common mechanisms with electrically induced LTD. These findings provide one of the first examples of LTD gating under the control of a G protein-coupled receptor that might lead to imbalanced synaptic plasticity and memory impairment following a nonphysiological elevation of extracellular serotonin.

Comparable studies

Other preclinical and animal studies on serotonin, most cited first.

Study Year Design Participants
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice 2021 Observational cohort
Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) 1987 Experimental study
Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models 2023 Experimental study
3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain 1987 Animal experiment
Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells 2006 In vitro laboratory study

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Serotonin Depression Neuroplasticity