Scientists at HHMI’s Janelia Research Campus have discovered a recent type of synapse within the tiny hairs on the surface of neurons.
The commonly missed protrusions called primary cilia contain special junctions that act as a shortcut for sending signals quickly and on to the cell’s nucleus, inducing changes to the cell’s chromatin that forms chromosomes.
“This special synapse represents a method to change what’s being transcribed or made within the nucleus, and that changes whole programs,” says Janelia Senior Group Leader David Clapham, whose team led the brand new research published September 1 in Cell. The consequences within the cell are usually not just short-term, he adds – some might be long-term. “It is sort of a recent dock on a cell that provides express access to chromatin changes, and that could be very vital because chromatin changes so many points of the cell.”
Synapses are well-known to occur between the axon of 1 neuron and the dendrites of other neurons, but had never been observed between the neuron’s axon and the first cilium. Janelia’s high-resolution microscopes and progressive tools enabled the researchers to see deep into the cell and cilia to look at the synapse, the signaling cascade contained in the cell, and the changes within the nucleus.
The invention of the ciliary synapse could help scientists higher understand how long-term changes in cells are communicated. The cilia, which extend from the cell’s interior, near the nucleus, to the outside, could provide a faster and more selective way for cells to perform these long-term changes, Clapham says.
This was all about seeing – and Janelia enables us to see like we couldn’t see before. It opens up loads of possibilities we hadn’t considered.”
David Clapham, Janelia Senior Group Leader
Imaging cilia
Nearly every cell in our body has a single primary cilium, which is probably going a vestige from our unicellular ancestors. Sporting signal-detecting receptors, cilia play a vital role in cell division during development. Some cilia, equivalent to those in our lungs or the tail on a sperm, also serve vital functions later in life.
Nevertheless, it was unclear why other cells in our bodies, including neurons, retained this hair-like, bacterium-sized protrusion into maturity. Scientists had largely ignored these cilia because they were difficult to see with traditional imaging techniques. But recently, higher imaging tools have sparked an interest in these tiny appendages.
Shu-Hsien Sheu, a senior scientist at Janelia and first creator of the brand new study, admits that, regardless that trained as a neuroscientist and neuropathologist, he only learned about cilia on neurons as a postdoc within the Clapham Lab. Intrigued, Sheu decided to take a greater have a look at the organelle in brain tissue, to see what he might learn.
Sheu used his expertise in focused ion beam-scanning electron microscopy, or FIB-SEM, to get an excellent have a look at the cilia. The high-powered microscope allowed the team to see that there was a connection, or synapse, between the neuron’s axon and the cilium protruding outside the cell body. The structural features of those connections resemble those present in known synapses, leading them to call these connections the “axon-cilium” synapse or “axo-ciliary” synapse.
Next, the team developed recent biosensors and chemical tools to check the function of this newly discovered structure. The researchers also used an emerging imaging modality – fluorescence lifetime imaging (FLIM) – to make higher measurements of biochemical events contained in the cilia. “I learned FLIM in the course of the pandemic to deal with a number of the technical challenges. It turned out to be a game changer,” Sheu says.
With these tools, the team was in a position to show step-by-step how the neurotransmitter serotonin is released from the axon onto receptors on the cilia. This triggers a signaling cascade that opens the chromatin structure and allows changes to genomic material within the cell’s nucleus. “Function is what makes static structures come alive,” Sheu says. “Once we were confident concerning the structural finding, we looked deeply into its functional properties.”
Sheu says HHMI’s curiosity-driven research philosophy enabled the invention, which can not have been possible in a standard research setting. “That is an excellent example of how we’re in a position to make observations into discoveries.”
Long-term changes
Since the signals passed across the ciliary synapse enable changes to genomic material within the nucleus, they’re likely answerable for longer-term changes in neurons than signals passed from axons to dendrites, say the researchers. These changes could last anywhere from hours to days to years, depending on the proteins the chromatin encodes.
The brand new research specifically checked out receptors for serotonin, a neurotransmitter widespread within the brain that plays a vital role in alertness, memory, and fear. There are not less than seven to 10 other receptors on cilia for various neurotransmitters that may now have to be examined. Cilia on other cells beyond the brain, just like the liver and kidney, also deserve a better look.
Down the road, a greater understanding of the role of those ciliary synapses and receptors could help scientists develop more selective medications. Drugs that concentrate on serotonin transporters are used to treat depression, while serotonin can be linked to our sleep-wake cycle.
“The whole lot we find out about biology could also be useful for people to steer higher lives,” Clapham says. “In the event you can work out how biology works, you possibly can sort things.”
Source:
Howard Hughes Medical Institute
Journal reference:
10.1016/j.cell.2022.07.026