UC Davis basic research shows electrical signals, not just genetics, impact nerve and muscle cell communication
Yesser Hadj Belgacem, postdoctoral fellow, Borodinsky and Olesya Visina, research associate, review results in their Shriner's Hospital laboratory.
How muscle cells communicate with the nerve cells that control them is one of the most-studied aspects in cell biology. Now, new research conducted by Laura Borodinsky at the UC Davis School of Medicine promises to rewrite textbook descriptions of how these important communications at the synaptic gap develop.
Scientists have long known that communication between neurons and skeletal muscle cells in an adult animal is controlled by the neurotransmitter acetylcholine. Transmission of electrical signals at the synapse results from the release of acetylcholine from the neuron that then binds to acetylcholine receptors located on the surface of the muscle cell. Scientists assumed muscle cells expressed only acetylcholine receptors. But new research findings published in the Jan. 2 issue of Proceedings of the National Academy of Sciences is changing that view, offering new opportunities to develop treatments for depression, schizophrenia and related neurodegenerative disorders.
“We found that early in development the skeletal muscle is capable of expressing a variety of neurotransmitter receptors,” says Borodinsky, assistant professor of physiology and membrane biology at UC Davis and lead author of the research study. “But over time, these other receptors disappear.”
Borodinsky, who joined UC Davis in July and holds a joint appointment as an investigator at the Institute for Pediatric Regenerative Medicine at Shriners Hospital in Sacramento, conducted the research with Nicholas Spitzer while she was at UC San Diego.
Their research challenges the long-held view that the early development of the neuromuscular junction is completely controlled by genetic factors. In 2004, Borodinsky and colleagues published a paper showing that the neurotransmitters ultimately expressed by mature neurons are regulated by early electrical activity and not solely by preprogrammed genetic information.
Laura Borodinsky's future work will focus on determining the interactions among epigenetic factors, genetics and electrical activity in nervous system development.
“We wondered if that was true for the other side of the synapse,” Borodinsky explains. Using the frog species Xenopus laevis as a model system, her study shows that the kind of receptors expressed by a mature muscle cell also depends on the electrical activity neurons are exposed to during development. “There is more plasticity than anybody thought,” she says.
Electrical activity has long been accepted as a relevant factor later in development, especially for the refinement of connections, Borodinsky notes. “Our findings suggest that it could be important at very early stages, as well,” she says. In fact, electrical activity has been recorded at very immature stages, prior to synapse formation. “We want to know what that electrical activity is doing there so early.”
Borodinsky says her future work will focus on determining the interactions among epigenetic factors, genetics and electrical activity in nervous system development. These studies, she says, will likely shed new light on neurodegenerative disorders in which there is an imbalance in neurotransmitter and/or receptor metabolism and function, such as depression and schizophrenia.
Borodinsky points out that there are already treatments that involve focal electrical stimulation that sometimes achieve good results. “It is possible that this stimulation is actually inducing changes in neurotransmitter and receptor expression,” she said. “If we can better understand the mechanisms by which patterns of electrical activity regulate synaptic transmission, the chances to improve the treatments of these kinds of diseases will be greater.”