Evidence for ion-mediated regulation of nerve endings via glial cells

Written by Courtney Johnson

A new study, conducted at Rockefeller’s Laboratory of Developmental Genetics (Rockefeller University, NY, USA), has provided novel evidence for a specific mechanism of action glial cells employ to alter the shape and function of specific neurons. Understanding such mechanisms of specificity may have an impact on therapeutic research for neural disorders. The findings were published recently in Cell.
It has already been suggested that glial cells may possess the ability to manipulate the shape of nerve endings and mold the function of neural cells, however, the mechanisms for such alterations remain, for the most part, unknown. Disruptions in the shape of neurons have been linked to disorders such as dementia, schizophrenia and Alzheimer’s disease.

“In the nervous system, shape is everything,” comments Shai Shaham (Rockefeller University) . “The shape a neuron takes dictates which other neurons it connects to and even the strength of those connections. But we know precious little about how that shape is dictated.”

The current study investigated a glial cell that encases the nerve endings of 12 different neurons in the roundworm Caenorhabditis elegans. Investigation into the methods used to alter the shape of these nerve endings revealed that the glial cell employed different molecular mechanisms for each neuronal cell type.

“The glial cells are, surprisingly, multilingual,” states A Singhvi. “They can interact with different neurons differently.”

One of the neurons investigated was a thermosensory neuron. Researchers determined that an ion transporter protein,termed KCC-3, is expressed on the surface of the glial cell, however, only on the surface near the thermosensory neuron. This resulted in alteration  of the shape of the thermosensory neuron without impacting the surrounding neuronal cell types.

In addition to this, an alteration of neuronal function was also demonstrated. C. elegans worms with defective KCC-3 were observed not to seek out environmental temperatures similar to those of their rearing environment, a characteristic exhibited within non-defective C. elegans worms.

“This idea that glial cells may directly mold neural functions is not new,” remarked Shaham. “Our findings are direct proof that it actually happens.”

Further results in the study indicated that the local ion concentration influences the shape and function of nerve endings. KCC-3 was determined to control the extracellular levels of chloride ions, which in turn then impact the function of the proteins within the affected neuronal cell type. These proteins play a role in cell-skeleton manipulation and thus affect cell shape.

In humans, KCC-3 is expressed in the ears, retina and Schwann cells. Mutations in the gene that produces KCC-3 result in sensory neuropathy with symptoms indicative of this peripheral nervous system involvement, such as, tingling, pain, numbness or weakness in the hands and feet. The KCC-3 protein itself is also present in the central nervous system, highlighting it’s potential relevance to mechanisms involved in disorders that are associated with neuronal shape defects, for example, Huntington’s disease and epilepsy.

A further study by the same group, published in Cell Reports, indicates that glial cells in C.elegans alter the shape of many different types of nerve endings, pointing to many other molecular mechanisms that have not yet been discovered.

The concept that glial cells can manipulate only one type of neuron via ion transportation without affecting the surrounding neurons is an exciting prospect for further research. Investigation of the other methods that glial cells employ to manipulate neuronal shape and function may be significant for therapeutic developments if these mechanisms of action are widely used throughout the nervous system.

Sources: Rockefeller University Press Release; Singhvi A, Liu B, Friedman CJ, Fong J, Lu Y, Huang X-Y, Shaham S. A glial K/Cl transporter controls neuronal receptive ending shape by chloride inhibition of an rGC. Cell doi:10.1016/j.cell.2016.03.026 (2016) (Epub ahead of print); Wallace SW, Singhvi A, Liang Y, Lu Y, Shaham S. PROS-1/prospero is a major regulator of the glia-specific secretome controlling sensory-neuron shape and function in C. elegans. Cell Reports doi:10.1016/j.celrep.2016.03.051 (2016) (Epub ahead of print).