Serotonin signaling at cilia synapses

Serotonin (5-HT) is a key neuromodulator influencing cognition, mood, and sleep, yet the structural and molecular mechanisms of serotonergic signaling remain incompletely understood. Recent findings have identified a novel mode of serotonergic transmission via axo-ciliary synapses, where serotonergic axons directly contact the primary cilia of hippocampal pyramidal neurons. These synapses facilitate localized 5-HT release, activating ciliary 5-HT6R receptors and triggering intracellular signaling cascades distinct from conventional synaptic mechanisms. This pathway leads to chromatin remodeling and transcriptional regulation, providing a direct link between serotonergic signaling and neuronal gene expression. Additional volume electron microscopy studies have revealed the prevalence of axo-ciliary contacts across different brain regions, suggesting a broad role in neuromodulation. Further investigation into axo-ciliary synapses may provide critical insights into serotonergic function and its implications for neuropsychiatric disorders.