Researchers at Baylor College of Medicine have unraveled the processes that give astrocytes, the most abundant glial cell in the brain, their special bushy shape, which is essential for brain function. They report in the newspaper. Nature that neural activity is necessary and sufficient for astrocytes to develop their complex form, and disruption of this developmental process results in disrupted brain function.
“Astrocytes play a variety of roles that are vital to proper brain function,” said first author Yi-Ting Cheng, a graduate student in Dr. Benjamin Deneen’s lab at Baylor. “For example, they support the activity of other essential brain cells, neurons; they participate in the formation and function of synapses, or neuron-to-neuron connections; they release neurotransmitters, chemicals that mediate neuronal communication; and they form the barrier hematoencephalic.”
In the adult brain, the bushy shape of astrocytes is fundamentally related to efficient brain function. The ends of the branching structure of astrocytes interact with neurons and regulate synaptic activity. “If the astrocytes lose their structure, then the synapses don’t behave correctly and brain function fails,” said Deneen, professor and Russell J. and Marian K. Blattner, MD, Chair of the Department of Neurosurgery and Director of the Cancer Neuroscience Center. at Baylor. He is also the corresponding author of the work. “Discovering how astrocytes acquire their complex, bushy structure is essential to understanding how the brain develops and functions, and may provide new insight into how neurodevelopmental conditions arise. In this study, we investigate the cells and processes that direct the development of the structure of astrocytes.”
Neurons lead the way
When astrocytes develop, neurons are already present and active, so do neurons influence how astrocytes take on their complex shape?
“We artificially activated or silenced neurons and determined whether this would speed up or delay astrocyte maturation,” Cheng said. “We found that neural activity is necessary and sufficient to drive the full maturation of astrocytes into a bush-shaped cell.”
So how do astrocytes receive the signals that direct them down the proper maturation path? Through various experimental approaches, the team discovered that neurons produce a neurotransmitter called GABA that binds to astrocytes via a molecule on their surface called GABA.B. receiver. “We knocked out GABAB. receptor on astrocytes and activated neurons. In this situation, neurons did not promote the development of a typical astrocyte shape, supporting the idea that neurons communicate with astrocytes via GABA.B. receptor to promote its maturation”.
“This finding was surprising and very interesting,” Deneen said. “Neurotransmitters such as GABA are known to signal between neurons at synapses, but we found that neurotransmitters also signal to astrocytes, influencing their development by triggering changes in their structure.”
Other experiments revealed more pieces of the puzzle of how neurons drive astrocytes to develop their bushy shape. “Neurons produce GABA, which binds to astrocytes through GABAB. receiver. In turn, this activates a series of events, including activating the expression of another receptor called Ednrb, which drives pathways that reshape cellular architecture within cells associated with cell shape,” Cheng said.
The researchers also investigated another mystery related to astrocyte development. They found that the regulation of GABA expressionB. receptor on astrocytes does not occur in the same way in different brain regions. “This result was totally unexpected,” Deneen said. “The GBAB. The receptor is universally required for astrocytes to develop their bushy form in all regions of the brain. How is it regulated differently in different areas of the brain?”
Through bioinformatics analyses, the researchers discovered that this regional regulation is conferred by two proteins, LHX2 in the cerebral cortex and NPAS3 in the olfactory bulb, through their specific regional interactions with the SOX9 and NFIA proteins, which are present in all astrocytes. where they regulate GABA.B. receptor expression. In the cortex, LHX2 only binds NFIA, whereas in the olfactory bulb, NPS3 only binds SOX9, allowing each to regulate GABA.B. receptor expression in a specific region of the brain.
Taken together, the findings suggest that astrocyte development and function involve a complex pattern of events and proteins that are triggered by the activity of neurons and that operate in a region-specific manner.
Estefania Luna-Figueroa, Junsung Woo, Hsiao-Chi Chen, Zhung-Fu Lee1, and Akdes Serin Harmanci, all from Baylor College of Medicine, also contributed to this work.
This work was supported by grants NS071153, AG071687, and NS096096 from the National Institutes of Health (NIH), the David and Eula Wintermann Foundation, NIH Shared Instrument Grants S10OD023469, S10OD025240, and P30EY002520, the Nucleus for Cytometry and Classification of Cells at Baylor College of Medicine with funding from the CPRIT Core Facilities Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574), and the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development No. of prize P50HD103555.
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