title: Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression.
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.
authors.affiliation: Neuroscience, Ottawa Hospital Research Institute, University of Ottawa Ottawa, ON, Canada.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
authors.affiliation: Neuroscience, Ottawa Hospital Research Institute, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa ON, Canada.
authors.forename: Faranak
authors.initials: F
authors.lastname: Vahid-Ansari
authors.affiliation: Neuroscience, Ottawa Hospital Research Institute, University of Ottawa Ottawa, ON, Canada ; Department of Cellular and Molecular Medicine, University of Ottawa Ottawa ON, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Luckhart
keywords: anxiety; depression; interneurons; prefrontal cortex; pyramidal neurons; raphe nuclei; serotonin receptors; transcription factors