Serotonin targets inhibitory synapses to induce modulation of network functions

TLDR

Serotonin (5‑HT) is a widespread neuromodulator whose cellular effects are well studied, yet the heterogeneous expression of its receptors across diverse neurons prevents predicting how global 5‑HT action will reshape neuronal network responses and motor behavior. The study aims to show that 5‑HT1A receptor modulation in the respiratory network mainly targets glycinergic inhibition. The authors used the respiratory network, a system of reciprocal synaptic inhibition, to assess how 5‑HT1A receptor activation modulates glycinergic synapses. Potentiation of glycinergic inhibition reorganizes the respiratory network, producing a distinct motor output that robustly counteracts opiate‑induced respiratory depression and stabilizes breathing rhythm during pain medication.

Abstract

The cellular effects of serotonin (5-HT), a neuromodulator with widespread influences in the central nervous system, have been investigated. Despite detailed knowledge about the molecular biology of cellular signalling, it is not possible to anticipate the responses of neuronal networks to a global action of 5-HT. Heterogeneous expression of various subtypes of serotonin receptors (5-HTR) in a variety of neurons differently equipped with cell-specific transmitter receptors and ion channel assemblies can provoke diverse cellular reactions resulting in various forms of network adjustment and, hence, motor behaviour. Using the respiratory network as a model for reciprocal synaptic inhibition, we demonstrate that 5-HT 1A R modulation primarily affects inhibition through glycinergic synapses. Potentiation of glycinergic inhibition of both excitatory and inhibitory neurons induces a functional reorganization of the network leading to a characteristic change of motor output. The changes in network operation are robust and help to overcome opiate-induced respiratory depression. Hence, 5-HT 1A R activation stabilizes the rhythmicity of breathing during opiate medication of pain.