Astrocyte-secreted chordin-like 1 regulates spine density after ischemic injury

Elena Blanco-Suarez,Nicola J Allen

doi:10.1038/s41598-022-08031-4

Abstract

Ischemic injury occurs when the brain is deprived of blood flow, preventing cells from receiving essential nutrients. The injury core is the brain region directly deprived and is surrounded by the peri-infarct area, the region with recovery potential. In the peri-infarct area neurons undergo acute loss of dendritic spines, which modifies synaptic plasticity and determines neuronal survival. Astrocytes can be protective or detrimental to the ischemic injury response depending on the specific stage, yet we lack clear understanding of the underlying mechanisms. Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse visual cortex. Given this plasticity-limiting function we asked if Chrdl1 regulates the response to ischemic injury, modelled using photothrombosis (PT). We find that Chrdl1 mRNA is upregulated in astrocytes in the peri-infarct area in both acute and sub-acute phases post-PT. To determine the impact of increased Chrdl1 on the response to PT we analyzed Chrdl1 knock-out mice. We find that absence of Chrdl1 prevents ischemia-induced spine loss in the peri-infarct area and reduces cell death in the core, without impacting gliosis. These findings highlight the important role of astrocyte-secreted proteins in regulating structural plasticity in response to brain ischemic injuries.

Highlights

Ischemic injury is characterized by the interruption of blood flow to a specific region of the brain
We previously identified chordin-like 1 (Chrdl1), which is enriched in expression in astrocytes in upper layers of the cortex and the striatum, as an astrocytesecreted protein that induces synapse maturation by recruiting GluA2 AMPA glutamate receptors to synaptic sites[20]
To determine if the upregulation of Chrdl[1] was astrocytic, and not due to upregulation from a non-astrocyte cell type, we used fluorescence in situ hybridization (FISH) in layers 2/3 of the visual cortex to analyze Chrdl[1] mRNA overlap with markers for astrocytes (Slc1a3, known as Glutamate Aspartate Transporter, GLAST) and neurons (Tubb3) in the peri-infarct area. This agreed with our previous study[20] where we found that Chrdl[1] was mainly expressed by astrocytes, and we verified that ischemic injury does not trigger upregulation of Chrdl[1] from a non-astrocyte cell population

Summary

Introduction

Ischemic injury is characterized by the interruption of blood flow to a specific region of the brain. A study blocking a different plasticity-limiting molecule that is expressed by neurons, PirB, found this manipulation promoted enhanced experience-dependent plasticity, and further proved beneficial in the context of ischemic stroke by reducing the size of the injury, improving motor recovery, and decreasing astrocyte r eactivity[22,23]. This suggests that targeting other endogenous plasticity-limiting molecules, such as Chrdl[1], may be beneficial in recovery from ischemic injuries

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Conclusion