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Apr 1

Research Byte: Don’t be fooled by appearances: A novel role for subsets of cortical astroglia

Research Bytes
Packard Center researchers describe a subset of cortical -astroglia with critical importance to neuron health
Dr. Jeffrey Rothstein

Neurons are the fundamental cells of the brain and spinal cord responsible for orchestrating our every move and thought, but the most abundant cells in the central nervous system (CNS) are astroglia.  Named for their star-like shape, it is a commonly held belief among research scientists that astroglia are functionally homogeneous—they all look alike... unlike neurons!. A new study published today in Nature Neuroscience, however, provides evidence to the contrary.  The work, led by Packard Center and Brain Science Institute Founder and Director Dr. Jeffrey Rothstein, identifies a subpopulation of cortical astroglia with a distinctive and critical role in supporting neuronal growth and communication. Understanding their function may have implications for the treatment of dementia and ALS and other degenerative diseases of the brain.

Glutamate, a neurotransmitter that facilitates cell-to-cell communication in the CNS, travels between cells via transporters.  All astrocytes express the glutamate transporter GLT1, but in varying amounts.  Originally seeking to differentiate astrocytes based on their levels of GLT1 expression, Rothstein and his team genetically modified mice so that their GLT1-positive astroglia would fluoresce red.  The researchers noticed, however, that when fluorescence was stimulated in a very specific spot within the gene, exactly 8.3kB away from the start of the gene, only a select population of astrocytes within the outer cortex of the brain fluoresced red.  Deciding to name these cells 8.3-astroglia, the team hypothesized that they might likely have a unique biological function. To investigate further, they isolated the 8.3-astroglia and measured which genes were highly expressed in them, but not in other astrocytes.  Among the genes discovered by the research team to be highly enriched in 8.3-astroglia were Lgr6 and Norrin

After confirming that the LGR6 receptor is located in 8.3-astroglia in both mice and humans using histological techniques, the investigators set out to determine the functional significance of LGR6 in these cells.  When the researchers generated animals that produced 50% less LGR6 receptor, they observed the negative consequences of decreased 8.3-astroglial numbers, a decline in the health of neurons, and thinning of the cortex.  Conversely, stimulation of LGR6 from neurons beneficially promoted astroglial growth, highlighting the importance of neuron-astroglia communication to cell survival in the cortex. Stimulation of the LGR6 receptor also resulted in increases production of astroglial Norrin.

Norrin is protein in the cerebral cortex that is made by astroglia. Mutations in Norrin lead to the rare neurodevelopmental disorder Norrie disease, commonly characterized by blindness, cognitive impairment, and psychological issues.  To directly measure the contributions of Norrin to the health of neurons, the scientists treated neurons with either normal Norrin or the damaged forms of Norrin that are found in Norrie disease.  While damaged Norrin had no effect, treatment with normal Norrin was beneficial to neurons.  “The principal functions of Norrin seems to be controlling the growth of neuronal spines, the processes on the ends of neurons by which they communicate with one another,” concludes Rothstein.  Verifying this result, the researchers generated mice that do not produce Norrin, and found that these animals had severely compromised neuronal spine morphology in the cerebral cortex and displayed behavioral deficits. To specifically study the importance of 8.3-astroglia-produced Norrin, the researchers then generated mice that expressed Norrin only in cortical 8.3-astroglia.  They found that production of Norrin in these cells alone was sufficient to rescue the abnormalities observed in mice that otherwise do not produce Norrin.

The implications of the present study are far-reaching. The work of the Packard Center team not only critically advances our understanding of the rare developmental disorder Norrie Disease, but according to Rothstein shows that Norrin, “is an interesting therapeutic avenue that is testable in ALS, dementias, and the many other disease in which neuronal spines are compromised.” The research also highlights how studying neuron-glia communication in detail can uncover novel mechanisms by which neurological diseases develop and progress.  Future directions for the investigators include experiments to better understand the Norrin pathway, and studying its relevance to ALS and dementias.  “Norrin is binding to a receptor on neurons,” says Rothstein. “We need to understand that receptor. There are a lot of openings for new research.”
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