Scientists at HHMI’s Janelia Research Campus discovered a new type of synapse in tiny hairs on the surface of neurons.
Often overlooked protrusions called primary cilia contain special junctions that act as a shortcut to send signals quickly and directly to the cell’s nucleus, causing changes in the cell’s chromatin that form chromosomes.
“This particular synapse represents a way to change what’s being transcribed or done in the nucleus, and that changes whole programs,” said Janelia, a senior leader in the David Clapham group, whose team led the new research, published Sept. 1 in cell. The effects in the cell aren’t just short-term, he adds — some can be long-term. “It’s like a new cell dock that gives express access to chromatin changes, and that’s very important because chromatin changes so many aspects of the cell.”
Synapses are known to occur between the axon of one neuron and the dendrites of other neurons, but have never been observed between the axon of a neuron and the primary cilia. Janelia’s high-resolution microscopes and innovative instruments allowed researchers to peer deep into the cell and cilia to observe the synapse, the signaling cascade inside the cell, and changes in the nucleus.
The discovery of the ciliary synapse could help scientists better understand how long-term changes are communicated in cells. Cilia, which extend from the inside of the cell, near the nucleus, to the outside, could provide a faster and more selective way for cells to make these long-term changes, Clapham says.
“It was all about seeing – and Janelia lets us see like we haven’t seen before,” says Clapham. “It opens up a lot of possibilities that we hadn’t thought of.”
Rendering of cilia
Almost every cell in our body has a single primary cilia, which is probably a remnant of our unicellular ancestors. Sporting signal-detecting receptors, cilia play an important role in cell division during development. Some cilia, such as those in our lungs or the tail of sperm, also serve important functions later in life.
However, it was not clear why other cells in our bodies, including neurons, retained this bacterium-sized hair-like protrusion to maturity. Scientists have largely overlooked these cilia because they are difficult to see with traditional imaging techniques. But recently, better imaging tools have sparked interest in these tiny appendages.
Shu-Hsien Sheu, senior scientist at Janelia and first author of the new study, admits that although he is trained as a neuroscientist and neuropathologist, he only learned about cilia on neurons as a postdoc at the Clapham lab. Intrigued, Sheu decided to take a closer look at the organelle in brain tissue to see what he could learn.
Sheu used his expertise in focused ion beam scanning electron microscopy, or FIB-SEM, to get a good look at the cilia. The powerful microscope allowed the team to see that there was a connection, or synapse, between the neuron’s axon and the cilium protruding from the cell body. The structural features of these connections resemble those found in known synapses, leading them to call these connections an “axon-cilia” synapse or an “axo-ciliary” synapse.
The team then developed new biosensors and chemical tools to study the function of this newly discovered structure. The researchers also used an emerging imaging modality—fluorescence lifetime imaging (FLIM)—to make better measurements of the biochemical events inside the cilia. “I learned FLIM during the pandemic to deal with some of the technical challenges. It turned out to be a game changer,” says Sheu.
With these tools, the team was able to show step-by-step how the neurotransmitter serotonin is released from the axon onto cilia receptors. This triggers a signaling cascade that opens up the chromatin structure and allows changes in the genomic material in the cell’s nucleus. “Function is what makes static structures come to life,” says Sheu. “Once we were confident in the structural finding, we took a closer look at its functional properties.”
Sheu says HHMI’s curiosity-based research philosophy has enabled discovery that might not have been possible in a traditional research environment. “This is a good example of how we can turn observations into discoveries.”
Because signals passed through the ciliary synapse allow changes in genomic material in the nucleus, they are likely responsible for longer-term changes in neurons than signals passed from axons to dendrites, the researchers said. These changes can last from hours to days or years, depending on the proteins that the chromatin encodes.
The new research specifically looked at receptors for serotonin, a neurotransmitter widely distributed in the brain that plays an important role in alertness, memory and fear. There are at least seven to 10 other cilia receptors for different neurotransmitters that now need to be investigated. The cilia of other cells outside the brain, such as the liver and kidney, also deserve a closer look.
Ultimately, a better understanding of the role of these ciliary synapses and receptors may help scientists develop more selective drugs. Drugs targeting serotonin transporters are used to treat depression, while serotonin is also linked to our sleep-wake cycle.
“Everything we learn about biology can be useful for people to lead better lives,” says Clapham. “If you can understand how biology works, you can fix things.”