AIS but not off-target varicosities predominantly contain presynaptic markers. A, Immunohistochemical analysis of VGAT localization in ChC varicosities in Nkx2.1-CreER;LSL-tGFP mice. Confocal images of a single optical section showing varicosities (green), VGAT (red), and AISs visualized by AnkG immunostaining (blue) in a P16 brain. White and yellow arrowheads indicate AIS and off-target varicosities, respectively. Filled and empty arrowheads show VGAT+ and VGAT- varicosities in ChC axons, respectively. Scale bar, 5 μm. B, The average percentage of VGAT-containing AIS and off-target varicosities in P16 ChCs. The percentage of VGAT-containing AIS varicosities is significantly higher than that of VGAT-containing off-target varicosities (n = 7 ChCs for each; ≥3 brains per condition; Student’s t test: **p < 0.001)h. Data are presented as mean ± SEM. C, Localization of Syp-YFP puncta in varicosities of transplanted ChCs. Confocal images of a single optical section showing AIS visualized by AnkG immunostaining (blue), Syp-YFP (green), and varicosities along the axon (red) in an EP16 brain. White and yellow arrowheads indicate AIS and off-target varicosities, respectively. Filled and empty arrowheads show Syp-YFP+ and Syp-YFP- varicosities in ChC axons, respectively. Scale bar, 5 μm. D, The average percentage of Syp-YFP-containing AIS and off-target varicosities in EP16 ChCs. The percentage of Syp-YFP containing AIS varicosities is significantly higher than that of Syp-YFP containing off-target varicosities (n = 6 ChCs; ≥3 brains; Student’s t test: ***p < 0.001)l. Data are presented as mean ± SEM. E, The average percentage of VGAT-containing AIS and off-target varicosities in P28 ChCs. The percentage of VGAT-containing AIS varicosities is significantly higher than that of VGAT-containing off-target varicosities (n = 7 ChCs for each; ≥3 brains per condition; Student’s t test: ***p < 0.001)°. Data are presented as mean ± SEM.
A unique inhibitory interneuron implicated in schizophrenia and epilepsy etc, seem to develop their connections differently than other types of neurons. Most cells’ axons reach out and form synapses on other cells’ dendrites or cell bodies, but chandelier cells exclusively inhibitory synapse on other cells’ axon initial segments (AIS), right where the cell begins to send its own signal down the axon. At this location, the chandelier cells have a greater impact on other cell’s behavior. “Chandelier cells are the final gatekeeper of the action potential,” said Dr. Taniguchi. “We believe this role makes them an especially important factor in controlling epilepsy, where over-excitement spreads throughout the brain unchecked.”
Using their own recently-developed genetic labeling techniques for tracking these cells in early development in mice, Taniguchi and his team observed that, like most neurons, the cells remodeled their axonal organization through development. They also found excessive axonal varicosities that have been considered morphologically synaptic structures. To investigate whether these varicosities actually contained synaptic molecules, the team expressed synaptic markers in the chandelier cells using transplantation techniques.
What they found was surprising. Only those varicosities that were associated with the AIS contained synapses – the rest appeared to be empty throughout development. This was also corroborated by their ultrastructures obtained with electron microscopy. These findings provide a big clue to understanding how this important cell type properly wires a unique circuit. Now the researchers must ask: what purpose do these empty varicosities service and what molecules help direct chandelier cells to recognize the AIS?
The team plans to use live cell imaging to explore the function of the empty varicosities in axonal wiring. “There must be some genes that are necessary and possibly also sufficient to guide the chandelier cell axons to this subcellular target,” said Andre Steineke, Ph.D., Postdoctoral Researcher. He explained that it’s likely that these genes do not function properly during development in patients suffering from schizophrenia, epilepsy, or other diseases. Once identified, they may be valuable targets for drug development. Future studies on the molecular and cellular mechanisms of chandelier cell wiring will uncover important insights into how inhibitory circuits are assembled during development. https://www.maxplanckflorida.org/news-and-media/news/distinct-wiring-mode-found-in-chandelier-cells/
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