May 28 @ 11:00 am – 12:00 pm
Seminar held in person only.
Dr. Shu-Hsien Sheu
Group Leader
Biohub
“A serotonergic axon-cilium synapses”
Chemical synapses are classically formed between axons and dendrites — yet we discovered that serotonergic axons also synapse directly onto neuronal primary cilia, organelles positioned at the nexus of the cell surface and the nucleus. Understanding what signals flow through this synapse, and how it operates in human neurons, is the focus of our work.
We previously showed, using enhanced focused ion beam–scanning electron microscopy (FIB-SEM) with optimally preserved ultrastructure, that brainstem serotonergic axons form synapses with the primary cilia of hippocampal CA1 pyramidal neurons — the axo-ciliary synapse. These cilia are selectively enriched in the ciliary-restricted serotonin receptor 5-HTR6, and optogenetic and chemogenetic stimulation of serotonergic axons drives serotonin release directly onto cilia. Ciliary 5-HTR6 activation engages a non-canonical Gαq/11–RhoA pathway that remodels nuclear actin and increases histone acetylation and chromatin accessibility, revealing a more direct route from neuromodulatory input to epigenetic state.
Building on this foundation, my group is now establishing the human biology of neuronal primary cilia and axo-ciliary synapses. We are developing human induced pluripotent stem cell derived neuronal models and quantitative imaging approaches, including fluorescence lifetime imaging, to probe ciliary second messenger signaling, alongside cryo–electron tomography to resolve their molecular architecture. In parallel, we are building high-throughput in vitro platforms to reconstitute axo-ciliary synapses, laying the groundwork for systematic interrogation of this synapse class in a human context.