Summary: Neuronal activity is necessary and sufficient for astrocytes to develop their bushy shape, which is fundamental for brain function. These results suggest that astrocyte development and function involve a complex pattern of events and proteins triggered by neuron activity, offering new insights into the mechanisms of brain development and potential causes of neurodevelopmental disorders.
Source: Baylor College of Medicine
Key points:
- Astrocytes are the most abundant glial cells in the brain and play a variety of roles essential for proper brain function. They support the activity of neurons, participate in the formation and functioning of synapses, release neurotransmitters and constitute the blood-brain barrier.
- Neuronal activity is both necessary and sufficient to drive the full maturation of astrocytes into a bushy shaped cell. Neurons communicate with astrocytes via GABAB receptor to promote their maturation, triggering changes in their structure and remodeling the cellular architecture inside cells associated with cell shape.
- The development and function of astrocytes involves a complex pattern of events and proteins triggered by neuronal activity, and which function in a region-specific manner. These findings offer new insights into the mechanisms of brain development and the potential causes of neurodevelopmental disorders.
Researchers at Baylor College of Medicine have uncovered the processes that give astrocytes, the most abundant glial cell in the brain, their distinctive bushy shape, fundamental to brain function.
They report in the newspaper Nature that neuronal activity is necessary and sufficient for astrocytes to develop their complex form, and the interruption of this developmental process results in disruption of brain functions.
“Astrocytes play a variety of roles that are vital for 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; participate in the formation and functioning of synapses or neuron-to-neuron connections; release neurotransmitters, chemicals involved in neuronal communication; and form the blood-brain barrier.
In the adult brain, the bushy shape of astrocytes is fundamentally linked to efficient brain function. The ends of the branching structure of astrocytes interact with neurons and regulate synaptic activity.
“If astrocytes lose their structure, synapses don’t behave properly and brain function goes awry,” said Deneen, professor and chair of Dr. Russell J. and Marian K. Blattner in the Department of Neurosurgery and director of the Center for Cancer. Neuroscience at Baylor. He is also the corresponding author of the book.
“Understanding how astrocytes acquire their complex, bushy structure is essential for understanding how the brain develops and functions and can provide new insights into how neurodevelopmental conditions emerge. In this study, we investigated the cells and processes that direct the development of astrocyte structure.
Neurons pave the way
When astrocytes develop, neurons are already present and active, so do neurons influence how astrocytes acquire their complex shape?
“We artificially activated or silenced neurons and determined whether that would speed up or slow down astrocyte maturation,” Cheng said. “We found that neural activity is both necessary and sufficient to drive the full maturation of astrocytes into a tuft-like cell.”
So how do astrocytes receive the signals that direct them on the right path to maturation? Through several 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 in astrocytes and activated neurons. In this situation, the neurons did not promote the development of a typical astrocyte shape, supporting the idea that neurons communicate with astrocytes via GABAB receptor to promote their 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 astrocytes, influencing their development by triggering changes in their structure.”
Further experiments have revealed other pieces of the puzzle of how neurons drive astrocytes to develop their bushy shape.
“Neurons produce GABA, which binds to astrocytes via GABAB receiver. This in turn activates a series of events, including triggering the expression of another receptor called Ednrb, which drives pathways that remodel cellular architecture inside cells associated with cell shape.” , Cheng said.
The researchers also investigated another mystery related to the development of astrocytes. They found that regulation of GABA expressionB receptor in astrocytes does not occur in the same way in different regions of the brain.
“This result was completely unexpected,” Deneen said. “The GABAB is universally required for astrocytes to develop their bushy shape in all regions of the brain. How is it regulated differently in different areas of the brain? »
Through bioinformatics analyses, the researchers found that this regional regulation is conferred by two proteins, LHX2 in the cerebral cortex and NPAS3 in the olfactory bulb through their region-specific interactions with the SOX9 and NFIA proteins, which are present in all astrocytes where they regulate GABA.B expression of receptors.
In the cortex, LHX2 only binds NFIA, while in the olfactory bulb NPS3 only binds SOX9, allowing each to regulate GABAB receptor expression in a specific region of the brain.
Taken together, the results suggest that astrocyte development and function involves a complex pattern of events and proteins triggered by neuron activity that function in a region-specific manner.
Estefania Luna-Figueroa, Junsung Woo, Hsiao-Chi Chen, Zhung-Fu Lee1 and Akdes Serin Harmanci, all of Baylor College of Medicine, also contributed to this work.
Funding: This work was supported by National Institutes of Health (NIH) grants NS071153, AG071687, and NS096096, the David and Eula Wintermann Foundation, NIH Shared Instrument Grants S10OD023469, S10OD025240, and P30EY002520, Cytometry, and Sorting Core from Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574), and the NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development under award number P50HD103555.
About this neuroscience research news
Author: Grace Gutierrez
Source: Baylor College of Medicine
Contact: Graciela Gutierrez – Baylor College of Medicine
Picture: Image is credited to Neuroscience News
Original research: Access closed.
“Inhibitory input directs astrocyte morphogenesis via the glial GABABR” by Yi-Ting Cheng et al. Nature
Abstract
Inhibitory input directs astrocyte morphogenesis via glial GABABR
Communication between neurons and glia plays an important role in establishing and maintaining higher-order brain functions.
Astrocytes are endowed with complex morphologies, placing their peripheral processes close to neuronal synapses and contributing directly to their regulation of brain circuitry.
Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unclear.
Here we show that the activity of inhibitory neurons is necessary and sufficient for astrocyte morphogenesis.
We found that the input of inhibitory neurons works via astrocytic GABAB receptor (GABABR) and that its suppression in astrocytes results in loss of morphological complexity in many brain regions and disruption of circuit function.
Expression of GABABR in developing astrocytes is region-specifically regulated by SOX9 or NFIA and deletion of these transcription factors leads to region-specific defects in astrocyte morphogenesis, which are conferred by interactions with transcription factors exhibiting region-restricted expression patterns.
Together, our studies identify the contributions of inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is tightly linked to activity-dependent processes.