How stress remodels the brain

Summary: A single, stressful event causes rapid and long-lasting retraction of astrocyte branches. Stress induces this change by halting the production of GluA1.

Source: SfN

Stress restructures the brain by halting the production of crucial ion channel proteins, according to research in mice recently published in Journal of Neuroscience.

Stress harms the brain and body in profound ways. One way is by altering astrocytes, the brain’s housekeepers tasked with mopping up neurotransmitters after they’ve been released into the synapse. On the cellular level, stress causes the branches of astrocytes to retract from the synapses they wrap around.

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The branches of astrocytes retract from synapses 3 hours after stress and remain retracted for 24 hours. The image is credited to Bender et al. JNeurosci 2020.

Bender et al. investigated what controlled astrocyte changes after mice experienced exposure to the urine of a fox, their natural predator. This single stressful event caused quick but long-lasting retraction of the astrocyte’s branches. Stress induces this change by halting the production of GluA1, an essential subunit of glutamate receptors. During a stressful event, the stress hormone norepinephrine suppresses a molecular pathway that normally culminates in the protein synthesis of GluA1. Without functional GluA1 or glutamate receptors, neurons and astrocytes lose their ability to communicate with each other.

About this neuroscience research article

Source:
SfN
Media Contacts:
Calli McMurray – SfN
Image Source:
The image is credited to Bender et al. JNeurosci 2020.

Original Research: Open access
“Emotional Stress Induces Structural Plasticity in Bergmann Glial Cells via an AC5-CPEB3-GluA1 Pathway”. Crhistian Luis Bender, Xingxing Sun, Muhammad Farooq, Qian Yang, Caroline Davison, Matthieu Maroteaux, Yi-shuian Huang, Yoshihiro Ishikawa and Siqiong June Liu.
Journal of Neuroscience doi:10.1523/JNEUROSCI.0013-19.2020.

Abstract

Emotional Stress Induces Structural Plasticity in Bergmann Glial Cells via an AC5-CPEB3-GluA1 Pathway

Stress alters brain function by modifying the structure and function of neurons and astrocytes. The fine processes of astrocytes are critical for the clearance of neurotransmitters during synaptic transmission. Thus, experience-dependent remodeling of glial processes is anticipated to alter the output of neural circuits. However, the molecular mechanism(s) that underlie glial structural plasticity are not known. Here we show that a single exposure of male and female mice to an acute stress produced a long-lasting retraction of the lateral processes of cerebellar Bergmann glial cells. These cells express the GluA1 subunit of AMPA-type glutamate receptors and GluA1 knockdown is known to shorten the length of glial processes. We found that stress reduced the level of GluA1 protein and AMPA receptor-mediated currents in Bergmann glial cells and these effects were absent in mice devoid of CPEB3, a protein that binds to GluA1 mRNA and regulates GluA1 protein synthesis. Administration of a β-adrenergic receptor blocker attenuated the reduction in GluA1 and deletion of adenylate cyclase 5 prevented GluA1 suppression. Therefore, stress suppresses GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway, and reduces the length of astrocyte lateral processes. Our results identify a novel mechanism for GluA1 subunit plasticity in non-neuronal cells, and suggest a previously unappreciated role for AMPA receptors in stress-induced astrocytic remodeling.

Significance statement

Astrocytes play important roles in synaptic transmission by extending fine processes around synapses. In this study, we showed that a single exposure to an acute stress triggered a retraction of lateral/fine processes in mouse cerebellar astrocytes. These astrocytes express GluA1, a glutamate receptor subunit known to lengthen astrocyte processes. We showed that astrocytic structural changes are associated with a reduction of GluA1 protein levels. This requires activation of β-adrenergic receptors and is triggered by noradrenaline released during stress. We identified adenylyl cyclase 5 as a downstream effector, an enzyme that elevates cAMP levels, and found that lowering GluA1 levels depends on CPEB3 proteins that bind to GluA1 mRNA. Therefore, stress regulates GluA1 protein synthesis via an adrenergic/adenylyl cyclase/CPEB3 pathway in astrocytes and remodels their fine processes.

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