Cited by 323Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

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Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression

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Albert, Paul R., Vahid-Ansari, Faranak, Luckhart, Christine·2014·Frontiers in Behavioral Neuroscience

DOI 10.3389/fnbeh.2014.00199PMC PMC4047678

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Abstract

Decreased serotonergic activity has been implicated in anxiety and major depression, and antidepressants directly or indirectly increase the long-term activity of the serotonin system. A key component of serotonin circuitry is the 5-HT1A autoreceptor, which functions as the major somatodendritic autoreceptor to negatively regulate the "gain" of the serotonin system. In addition, 5-HT1A heteroreceptors are abundantly expressed post-synaptically in the prefrontal cortex (PFC), amygdala, and hippocampus to mediate serotonin actions on fear, anxiety, stress, and cognition. Importantly, in the PFC 5-HT1A heteroreceptors are expressed on at least two antagonist neuronal populations: excitatory pyramidal neurons and inhibitory interneurons. Rodent models implicate the 5-HT1A receptor in anxiety- and depression-like phenotypes with distinct roles for pre- and post-synaptic 5-HT1A receptors. In this review, we present a model of serotonin-PFC circuitry that integrates evidence from mouse genetic models of anxiety and depression involving knockout, suppression, over-expression, or mutation of genes of the serotonin system including 5-HT1A receptors. The model postulates that behavioral phenotype shifts as serotonin activity increases from none (depressed/aggressive not anxious) to low (anxious/depressed) to high (anxious, not depressed). We identify a set of conserved transcription factors including Deaf1, Freud-1/CC2D1A, Freud-2/CC2D1B and glucocorticoid receptors that may confer deleterious regional changes in 5-HT1A receptors in depression, and how future treatments could target these mechanisms. Further studies to specifically test the roles and regulation of pyramidal vs. interneuronal populations of 5-HT receptors are needed better understand the role of serotonin in anxiety and depression and to devise more effective targeted therapeutic approaches.

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Authors: Albert, P. R., Vahid-Ansari, F., & Luckhart, C.
Affiliations: University of Ottawa (CA)
Corresponding author: Albert, Paul R.
ORCID: Albert, Paul R.
Vahid-Ansari, Faranak
Luckhart, Christine
Venue: Frontiers in Behavioral Neuroscience
Publisher: Frontiers Media SA
Published: 2014-06-06
Volume: 8
Pages: 199-199
ISSN: 1662-5153 (ISSN-L)
DOI: 10.3389/fnbeh.2014.00199
PMC: PMC4047678
OpenAlex: W2092933199
Cited by: 321
References: 139
Citations by year: 2026: 27 · 2025: 31 · 2024: 27 · 2023: 24 · 2022: 24 · 2021: 21 · 2020: 24 · 2019: 27 · 2018: 30 · 2017: 33 · 2016: 19 · 2015: 26 · 2014: 8
FWCI: 3.27
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Canadian Institutes of Health Research (123426_1, 115098_1)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: serotonin, 5-HT1A receptor, prefrontal cortex, anxiety, depression, autoreceptors, heteroreceptors, pyramidal neurons, interneurons, DEAF1, glucocorticoid receptor, genetic mouse models, antidepressant targets

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Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression

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