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

The DOI matches its Crossref record; 139 of the 139 references it cites were found in a registry or an index.

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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Crossref · 10.3389/fnbeh.2014.00199

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Figure 1 Early post-natal 5-HT-PFC circuitry in anxiety models. Shown are the components of the Raphe 5-HT-PFC circuit in animals during the early post-natal period with no, low, normal or high levels of 5-HT neurotransmission as indicated. Evidence from genetic mouse models (Table 1) supports the importance of alterations in early post-natal circuitry in generating the adult anxiety phenotype. The model shows 5-HT neurons (orange) projecting to prefrontal cortex GABAergic interneurons (red) and glutamatergic pyramidal neurons (green) with transmitter release illustrated as small squares of the same colors. Although 5-HT neurons are shown projecting separately to glutamatergic or GABAergic PFC neurons to illustrate the different activities of these pathways, the same 5-HT neuron may innervate both cells with different efficiency synapses or varicosities (Bang et al., 2012). The presence of 5-HT1A (yellow), 5-HT2A (orange) and GABA-A receptors (red) is shown, as well as the response in the target neurons (clouds), stimulatory (+) or inhibitory (−). The effect of chronic stress to stimulate pyramidal output is also indicated. It is postulated that 5-HT1A-mediated inhibition in the early post-natal period and perhaps adult is greater in interneurons than pyramidal neurons and that increased pyramidal neuronal activity triggers the anxiety phenotype, especially during the early post-natal period.
Figure 1 Early post-natal 5-HT-PFC circuitry in anxiety models. Shown are the components of the Raphe 5-HT-PFC circuit in animals during the early post-natal period with no, low, normal or high levels of 5-HT neurotransmission as indicated. Evidence from genetic mouse models (Table 1) supports the importance of alterations in early post-natal circuitry in generating the adult anxiety phenotype. The model shows 5-HT neurons (orange) projecting to prefrontal cortex GABAergic interneurons (red) and glutamatergic pyramidal neurons (green) with transmitter release illustrated as small squares of the same colors. Although 5-HT neurons are shown projecting separately to glutamatergic or GABAergic PFC neurons to illustrate the different activities of these pathways, the same 5-HT neuron may innervate both cells with different efficiency synapses or varicosities (Bang et al., 2012). The presence of 5-HT1A (yellow), 5-HT2A (orange) and GABA-A receptors (red) is shown, as well as the response in the target neurons (clouds), stimulatory (+) or inhibitory (−). The effect of chronic stress to stimulate pyramidal output is also indicated. It is postulated that 5-HT1A-mediated inhibition in the early post-natal period and perhaps adult is greater in interneurons than pyramidal neurons and that increased pyramidal neuronal activity triggers the anxiety phenotype, especially during the early post-natal period.CC BY · PubMed Central
Figure 2 Adult 5-HT-PFC circuitry in depression models. Shown are the components of the Raphe 5-HT-PFC circuit in adult animals with no, low, normal or high levels of 5-HT neurotransmission as indicated. The model shows 5-HT neurons (orange) projecting to prefrontal cortex GABAergic interneurons (red) and glutamatergic pyramidal neurons (green) with transmitter release illustrated as small squares of the same colors. The presence of 5-HT1A (yellow), 5-HT2A (orange), AMPA-glutamate (green) and GABA-A receptors (red) is shown, as well as the response in the target neurons (clouds), stimulatory (+) or inhibitory (−). The effect of stress to stimulate pyramidal output is also indicated. It is postulated that 5-HT1A-mediated inhibition in adulthood becomes predominant in pyramidal neurons compared to interneurons, and that reduced activity of target pyramidal neurons elicits depression during adulthood.
Figure 2 Adult 5-HT-PFC circuitry in depression models. Shown are the components of the Raphe 5-HT-PFC circuit in adult animals with no, low, normal or high levels of 5-HT neurotransmission as indicated. The model shows 5-HT neurons (orange) projecting to prefrontal cortex GABAergic interneurons (red) and glutamatergic pyramidal neurons (green) with transmitter release illustrated as small squares of the same colors. The presence of 5-HT1A (yellow), 5-HT2A (orange), AMPA-glutamate (green) and GABA-A receptors (red) is shown, as well as the response in the target neurons (clouds), stimulatory (+) or inhibitory (−). The effect of stress to stimulate pyramidal output is also indicated. It is postulated that 5-HT1A-mediated inhibition in adulthood becomes predominant in pyramidal neurons compared to interneurons, and that reduced activity of target pyramidal neurons elicits depression during adulthood.CC BY · PubMed Central

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  1. Newman-Tancredi, 2012, Gene polymorphism at serotonin 5-HT1A receptors: moving towards personalized medicine for psychosis and mood deficits, 337

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Metadata

Authors
Albert, P. R., Vahid-Ansari, F., & Luckhart, C.
Affiliations
University of Ottawa (CA)
Corresponding author
Albert, Paul R.
ORCID
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
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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