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

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

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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  • Up-regulated serotonin 1A receptors may result from a 5-HT1A gene promoter polymorphism that causes overexpression of autoreceptors.

    “Up-regulated serotonin 1A receptors may result from a 5-HT1A gene promoter polymorphism that causes overexpression of autoreceptors as a result of less binding of inhibitory transcription factors in serotonin neurons (120, 121).”

    From A brain-centric model of suicidal behavior (2020) · cites this paper as [120]

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Authors
Albert, P. R., Vahid-Ansari, F., & Luckhart, C.
Affiliations
University of Ottawa (CA)
Corresponding author
Albert, Paul R.
Venue
Frontiers in Behavioral Neuroscience
Published
2014-06-06
Volume
8
Pages
199-199
ISSN
1662-5153 (ISSN-L)
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
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 › 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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