When was the last time you made an exciting new connection? At an international conference, the coffee shop, or social media? A welcoming new study now provides evidence that brain cells don’t go to these lengths or even have to take a standard synaptic approach; instead, they use a connection – an axo-ciliary synapse – that short circuits neurotransmission to modify histone acetylation and chromatin accessibility!
A connective collaboration led by David E. Clapham (Janelia Research Campus at Howard Hughes Medical Institute) knew that mature neurons and glia in the brain retained their primary cilia and that these membrane-bound organelles expressed G-protein-coupled receptors (GPCRs) for neurotransmitters such as dopamine and serotonin (5-HT), whose loss impairs learning abilities. Chemical synapses between axons and dendrites typically mediate neuronal intercellular communication; but could ciliary signaling events make a new type of connection to support communication in the brain?
Let’s hear from Sheu and colleagues on how neurons don’t need social media to make new and exciting connections:
- Enhanced focused ion beam-scanning electron microscopy reveals the existence of an axo-ciliary synapse between serotonergic axons from the brainstem raphe nuclei and primary cilia of hippocampal CA1 pyramidal neurons
- Cilia possess a ciliary-restricted serotonin receptor – 5-hydroxytryptamine receptor 6 (5-HTR6) – that lies adjacent to serotonergic synapse components
- A cilia-targeted serotonin sensor demonstrates that the opto- and chemo-genetic stimulation of serotonergic axons prompts the release of serotonin onto the cilia to evoke nuclear signaling distinct to plasma membrane signaling
- Axo-ciliary synapses may be more analogous to immunological synapses
- Serotonin stimulation of ciliary 5-HTR6 activates a non-canonical Gαq/11-RhoA pathway in cilia, in which RhoA modulates nuclear actin and triggers epigenetic programming event distinct from classical neuronal signaling
- RhoA activity increases histone acetylation (H4K5 but not H3K27) and chromatin accessibility to alter transcription and modulate hippocampal function
- 5-HTR6 axo-ciliary synapse oscillation may induce chromatin remodeling during sleep/wake cycles, which impacts learning and memory
- Ablation of the Gαq/11-RhoA pathway reduces chromatin accessibility in hippocampal CA1 pyramidal neurons, as measured using a modified ATAC-see protocol in fixed mouse brain sections
- RhoA activity increases histone acetylation (H4K5 but not H3K27) and chromatin accessibility to alter transcription and modulate hippocampal function
Overall, these rather affable new findings suggest that axo-ciliary synapses may “short-circuit” neurotransmission to alter the epigenetic state of postsynaptic neurons to alter transcriptional output in response to environmental cues. Future studies to evaluate how epigenetic alterations affect learning and memory may require the characterization of chromatin accessibility over time and a better understanding of the genes and proteins that affect the relevant circuitry
“This special synapse represents a way to change what is being transcribed or made in the nucleus, and that changes whole programs,” says study leader David E. Clapham. “It is like a new dock on a cell that gives express access to chromatin changes, and that is very important because chromatin changes so many aspects of the cell.”
Check out this epigenetic short-circuit in Cell, September 2022.