Photo: Bryan Goodchild
A study by Dorothy P. Schafer, PhD, and Travis E. Faust, PhD, at UMass Chan Medical School, explains how two different cell types in the brain—astrocytes and microglia—communicate in response to changes in sensory input to remodel synapses, the connections between neurons.
Published in Cell, these findings are in an emerging area of interest for neurobiologists who want to understand how different cells in the brain interact to rewire the brain. This novel mechanism has the potential to be targeted by translational scientists hoping to one day prevent synaptic damage incurred during neurodegenerative diseases such as Alzheimer’s or ALS as well as age-related cognitive decline. It may also lead to new insights into neurodevelopmental and psychiatric disorders such as autism and schizophrenia, where the brain’s circuit refinement process may have been compromised during development.
“The brain is comprised of billions of cells that must in some way coordinate with each other to achieve appropriate brain wiring,” said Dr. Schafer, the Molly McGovern Chair in Biomedical Research and associate professor of neurobiology. “Understanding how all these cells coordinate is key. Here, we provide new insight into how non-neuronal cells called glial cells communicate to rewire brain circuits during development, which we think has relevance to a host of neurodegenerative and neurodevelopmental disorders where brain circuits are inappropriately remodeled.”
As the brain develops, neural circuits are refined and pruned in response to sensory stimuli received from the environment. If too many neural synapses are allowed to develop, neural networks cannot function properly, explained study co-author Dr. Faust, instructor in neurobiology. Autism is one neurodevelopmental disorder that is believed to be caused by a lack of synaptic pruning. Patients with schizophrenia have also been shown to have too few synapses in certain parts of the brain and too many in other parts.
Conversely, many neurodegenerative diseases such as Alzheimer’s and ALS are characterized by degradation and destruction of synapses where unchecked remodeling of synaptic connections is thought to cause cognitive and functional decline. Protecting these synapses from dysregulated synapse remodeling could prove to be beneficial for patients suffering from these diseases.
“This study shows how two different glial subtypes called astrocytes and microglia work in tandem to remove or ‘prune away’ synapses in the cortex after changing sensory experience,” said Schafer.
This study builds on a previous study by the Schafer lab published in Nature Neuroscience in 2019 where they modified the sensory experience of developing mice.
“Even a subtle change in the animal’s sensory experience in early development had a profound effect on brain wiring,” said Schafer.
Schafer and Faust have now shown how this re-wiring is achieved.
“You can think of astrocytes as densely packed bushes with millions of tiny branches that touch individual synapses and fill in all the gaps in the brain between neurons,” said Schafer.
In contrast, microglia are resident immune cells that monitor the brain and normally eat or engulf synapses.
“We show that microglia secrete molecules called Wnts, which signal to the astrocytes,” said Faust. “This signaling causes astrocytes to move their tiny branches away from synapses, which then allows microglia to swoop in and engulf the synapses.”
The key signaling molecule, Wnt, is a family of proteins secreted by cells that are crucial for numerous biological processes, including embryonic development, tissue homeostasis, stem cell regulation and cellular differentiation. In this setting, the Wnt protein acts as a signal to the astrocytes to move away and expose the synapses. This leaves the microglia free to move in and engulf the exposed and inactive synapses.
The implications for these findings are broad, said Schafer.
“So much remodeling happens in the brain during development as we experience the world around us and these sensory experiences change,” said Schafer. “One could imagine similar things are happening in other contexts such as learning and memory or during sleep. We are also looking into how this may be involved in disorders such as autism and schizophrenia where these remodeling processes may go awry or where they are aberrantly upregulated at the wrong time and place to cause loss of synaptic connections and cognitive decline in neurodegenerative diseases such as Alzheimer’s. Understanding how these processes may be involved in disease is one of our important next steps.”
Funding for this study was provided by the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Massachusetts Life Sciences Center, and the Adelson Medical Research Foundation.
