New research led by the Lippincott-Schwartz Lab shows that a network of subcellular structures similar to those responsible for propagating molecular signals that make muscles contract are also responsible for transmitting signals in the brain that may facilitate learning and memory.
“Einstein said that when he uses his brain, it is like he is using a muscle, and in that respect, there is some parallel here,” says Janelia Senior Group Leader Jennifer Lippincott-Schwartz. “The same machinery is operating in both cases but with different readouts.” The research appears in the journal Cell.
The first clue about the possible connection between brain and muscle cells came when Janelia scientists noticed something strange about the endoplasmic reticulum, or ER – the membranous sheets and folds inside cells that are crucial for many cellular functions.
Research scientist Lorena Benedetti was tracking molecules at high resolution along the surface of the ER in mammalian neurons when she saw that the molecules were tracing a repeating, ladder-like pattern along the entire length of the dendrites.
Around the same time, Senior Group Leader Stephan Saalfeld alerted Lippincott-Schwartz to high-resolution 3D electron microscopy images of neurons in the fly brain where the ER was also forming regularly spaced, transversal structures.
The ER normally appears like a huge, dynamic net, so as soon as Lippincott-Schwartz saw the structures, she knew her lab needed to figure out what they were for.
“In science, structure is function,” says Lippincott-Schwartz, who also heads Janelia’s 4D Cellular Physiology research area. “This is an unusual, beautiful structure that we are seeing throughout the whole dendrite, so we just had this feeling that it must have some important function.”
The researchers, led by Benedetti, started by looking at the only other area of the body known to have similar, ladder-like ER structures: muscle tissue. In muscle cells, the ER and the plasma membrane – the outer membrane of the cell – meet at periodic contact sites, an arrangement controlled by a molecule called junctophilin.
Using high-resolution imaging, the researchers discovered that dendrites also contain a form of junctophilin that controls contact sites between their ER and plasma membrane. Further, the team found that the same molecular machinery controlling calcium release at muscle cells’ contact sites – where calcium drives muscle contraction – was also present at dendrite contact sites – where calcium regulates neuronal signalling.
Because of these clues, the researchers had a hunch that the molecular machinery at the dendritic contact sites must also be important for transmitting calcium signals, which cells use to communicate. They suspected that the contact sites along the dendrites might act like a repeater on a telegraph machine: receiving, amplifying, and propagating signals over long distances. In neurons, this could explain how signals received at specific sites on dendrites are relayed to the cell body hundreds of micrometres away.
“How that information travels over long distances and how the calcium signal gets specifically amplified was not known,” says Benedetti. “We thought that ER could play that role, and that these regularly distributed contact sites are spatially and temporally localised amplifiers: they can receive this calcium signal, locally amplify this calcium signal, and relay this calcium signal over a distance.”
The researchers found that this process is triggered when a neuronal signal causes calcium to enter the dendrite through voltage-gated ion channel proteins, which are positioned at the contact sites. Although this initial calcium signal dissipates quickly, it triggers the release of additional calcium from the ER at the contact site.
Source: Howard Hughes Medical Institute
