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.
Highlights
DEPRESSION AND ANXIETY: ROLES OF SEROTONIN AND PREFRONTAL CORTEX (PFC) Depression and anxiety are complex and heterogeneous disorders with a global disease burden that is steadily increasing and has currently surpassed most other major diseases (Whiteford et al, 2013)
INTEGRATED MODEL OF 5-HT-PREFRONTAL CIRCUITRY IN ANXIETY AND DEPRESSION Recent and increasingly sophisticated mouse genetic models have resulted in a more precise dissection of the roles of 5-HT activity, and 5-HT1A autoreceptors vs. heteroreceptors in anxietyand depression-like behavior in rodents. These models have been examined for their anxiety and depression-like behavioral phenotypes and have shown that:
Post-natal modulation of the 5-HT system can produce lifelong changes in anxiety/stress reactivity. Both pre- and post-synaptic 5-HT1A receptors contribute to anxiety and depression phenotypes, often in opposite ways
Summary
DEPRESSION AND ANXIETY: ROLES OF SEROTONIN AND PREFRONTAL CORTEX (PFC) Depression and anxiety are complex and heterogeneous disorders with a global disease burden that is steadily increasing and has currently surpassed most other major diseases (Whiteford et al, 2013). The effect of the indicated genetic model on target gene expression (−, none; +, normal; ++, increased; +X, increased by X%) at indicated developmental time [embryo, early post-natal (PN) or adult] and adult behavior phenotype or response to SSRI are indicated.
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call