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.

Keywords: anxiety; depression; interneurons; prefrontal cortex; pyramidal neurons; raphe nuclei; serotonin receptors; transcription factors.

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 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.