5-HT1A Receptor-Mediated Autoinhibition and the Control of Serotonergic Cell Firing.

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.