The glia were thought of as support cells, but they have turned out to play roles in promoting normal neuronal and synaptic function. Now, for the first time UNC School of Medicine scientist Katie Baldwin, PhD, and colleagues revealed a central role of the glial protein hepaCAM in building the brain and affecting brain function early in life.
Their findings are published in Neuron in a paper titled “HepaCAM controls astrocyte self-organization and coupling.”
“Astrocytes extensively infiltrate the neuropil to regulate critical aspects of synaptic development and function,” write the researchers. “This process is regulated by transcellular interactions between astrocytes and neurons via cell adhesion molecules. How astrocytes coordinate developmental processes among one another to parse out the synaptic neuropil and form non-overlapping territories is unknown. Here we identify a molecular mechanism regulating astrocyte-astrocyte interactions during development to coordinate astrocyte morphogenesis and gap junction coupling.”
“Both astrocyte tiling and communication through gap junctions are disrupted in different brain disorders and following injury, suggesting these features are important for normal brain function,” explained Baldwin, the corresponding author, member of the UNC Neuroscience Center, and assistant professor in the UNC Department of Cell Biology and Physiology. “But prior to our study, it was unknown how astrocytes established their territories and whether there was a link between astrocyte territory and gap junction communication, also known as coupling.”
In the current study, the researchers focused on hepaCAM, a protein abundantly expressed on the astrocyte membranes. They created a transgenic rodent model so the animals did not express any hepaCAM protein in astrocytes. They used the model along with genetic and imaging techniques to study the developing astrocytes.
“Deleting hepaCAM from astrocytes disrupted astrocyte territories and impaired gap junction coupling. Essentially, these astrocytes no longer do a good job of communicating with their neighbors,” Baldwin said. “We also found that, even though we did not make any disruptions to neurons, loss of hepaCAM in astrocytes altered the balance of synaptic excitation and inhibition.”
“We think our findings have important implications for understanding the pathogenesis of MLC, as well as the general role of astrocyte dysfunction as a driving cause of neurological disorders, such as epilepsy,” Baldwin said.
Baldwin conducted this work while a postdoctoral fellow in Cagla Eroglu’s lab at Duke University before joining UNC-Chapel Hill this past spring. Her lab will continue to focus on the impact of hepaCAM mutations on astrocyte function.
“We are building on this research to explore the bigger question of how astrocytes balance their connections with other cell types in the brain,” she said, “with the goal of understanding how problems in astrocytes cause disease in humans, and how we might help people with these serious and complex disorders.”
“Therefore our findings suggest that disruption of astrocyte self-organization mechanisms could be an underlying cause of neural pathology,” concluded the researchers.