5-HT_1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing

Abstract

The idea that serotonergic synaptic transmission plays an essential role in the control of mood and the pharmacotherapy of anxiety and depression is one of the cornerstones of modern biological psychiatry. As a result, there is intense interest in understanding the mechanisms controlling the activity of serotonin-synthesizing (serotonergic) neurons. One of the oldest and most durable ideas emerging from this work is that serotonergic neurons are capable of autonomously regulating their own basal firing rate. Serotonergic neurons express on their surface 5-HT1A receptors (autoreceptors) that, when activated, induce the opening of potassium channels that hyperpolarize and thereby inhibit cell firing. Activity-dependent release of serotonin within serotonergic nuclei is thought to activate these autoreceptors, thus completing an autoinhibitory feedback loop. This concept, which was originally proposed in the 1970s, has proven to be enormously fruitful and has guided the interpretation of a broad range of clinical and preclinical work. Yet, remarkably, electrophysiological studies seeking to directly demonstrate this phenomenon, especially in in vitro brain slices, have produced mixed results. Here, we critically review this work with a focus on electrophysiological studies, which directly assess neuronal activity. We also highlight recent work suggesting that 5-HT1A receptor-mediated autoinhibition may play other roles in the control of firing besides acting as a feedback regulator for the pacemaker-like firing rate of serotonergic neurons.

Disruption of auto-inhibition underlies conformational signaling of ASIC1a to induce neuronal necroptosis

“…Auto-inhibition is a widespread and often constitutive mechanism that represses spontaneous activation of a potentially damaging signal 34 . Intramolecular auto-inhibition has been welldescribed for many receptors and kinases, such as 5-HT 1A receptor, EphB2 receptor, CaMKII, and Ca 2+ -ATPase [35][36][37][38][39] , as well as ion channels 40 . Auto-inhibition often involves the inhibitory domain juxtaposing and sterically masking the active domain, and unmasking is achieved by a conformational change during activation 34 .…”

Mechanisms of 5‐HT1A receptor‐mediated transmission in dorsal raphe serotonin neurons

“…; Andrade et al . ). Release of serotonin can activate inhibitory Gα i/o‐ coupled 5‐HT 1A autoreceptors that inhibit serotonergic neuron impulse activity through the opening of inwardly rectifying potassium (GIRK) channels (Aghajanian & Lakoski, ; De Vivo & Maayani, ; Pan & Williams, ; Pan et al .…”

Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study

“…For example, activation of somatodendritic receptors by serotonin or 5-HT 1A receptor agonists decreases the firing of serotonin neurons in the raphe, and, consequently decreases its terminal release6. This decrease is thought to be partially responsible for the delay in onset of the therapeutic action of selective serotonin reuptake inhibitors (SSRI) antidepressants5.…”