Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression
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 au...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-06-01
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| Series: | Frontiers in Behavioral Neuroscience |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00199/full |
| _version_ | 1828931303950516224 |
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| author | Paul R Albert Faranak eVahid-Ansari Faranak eVahid-Ansari Christine eLuckhart Christine eLuckhart |
| author_facet | Paul R Albert Faranak eVahid-Ansari Faranak eVahid-Ansari Christine eLuckhart Christine eLuckhart |
| author_sort | Paul R Albert |
| collection | DOAJ |
| description | 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. glial 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. |
| first_indexed | 2024-12-14T00:45:39Z |
| format | Article |
| id | doaj.art-cbaf4d9170c24ff18e8ce89e064a28c0 |
| institution | Directory Open Access Journal |
| issn | 1662-5153 |
| language | English |
| last_indexed | 2024-12-14T00:45:39Z |
| publishDate | 2014-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Behavioral Neuroscience |
| spelling | doaj.art-cbaf4d9170c24ff18e8ce89e064a28c02022-12-21T23:24:10ZengFrontiers Media S.A.Frontiers in Behavioral Neuroscience1662-51532014-06-01810.3389/fnbeh.2014.0019990869Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expressionPaul R Albert0Faranak eVahid-Ansari1Faranak eVahid-Ansari2Christine eLuckhart3Christine eLuckhart4University of OttawaUniversity of OttawaUniversity of OttawaUniversity of OttawaUniversity of OttawaDecreased 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. glial 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.http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00199/fullAnxietyDepressionInterneuronsPrefrontal CortexRaphe NucleiPyramidal neurons |
| spellingShingle | Paul R Albert Faranak eVahid-Ansari Faranak eVahid-Ansari Christine eLuckhart Christine eLuckhart Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression Frontiers in Behavioral Neuroscience Anxiety Depression Interneurons Prefrontal Cortex Raphe Nuclei Pyramidal neurons |
| title | Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression |
| title_full | Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression |
| title_fullStr | Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression |
| title_full_unstemmed | Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression |
| title_short | Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression |
| title_sort | serotonin prefrontal cortical circuitry in anxiety and depression phenotypes pivotal role of pre and post synaptic 5 ht1a receptor expression |
| topic | Anxiety Depression Interneurons Prefrontal Cortex Raphe Nuclei Pyramidal neurons |
| url | http://journal.frontiersin.org/Journal/10.3389/fnbeh.2014.00199/full |
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