Astrocyte CCN1 stabilizes neural circuits in the adult brain
Article meta
Article Date: 17 December 2025
Article URL: https://www.nature.com/articles/s41586-025-09770-w
Article Image: https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-025-09770-w/MediaObjects/41586_2025_9770_Fig1_HTML.png
Summary
This study identifies CCN1 (also called CYR61), a matricellular protein secreted by astrocytes, as a key factor that actively stabilises neural circuits in the adult mouse visual cortex. CCN1 expression in astrocytes rises with development and is reduced after paradigms that re-open plasticity (dark rearing or monocular deprivation). Increasing CCN1 in juvenile astrocytes prematurely limits large-scale circuit remodelling, while deleting Ccn1 from adult astrocytes reintroduces plasticity. Mechanistically, CCN1 acts on multiple cell types — excitatory and inhibitory neurons, oligodendrocyte lineage cells and microglia — to decrease excitatory drive onto pyramidal neurons, promote maturation of parvalbumin interneurons and perineuronal nets (PNNs), and drive oligodendrocyte differentiation and local myelination. A point mutation (D125A) that prevents CCN1 binding to αVβ3/αVβ5 integrins blocks certain CCN1 effects (notably on remodelling and aggrecan), implicating integrin signalling as an important pathway. Functionally, loss of astrocyte CCN1 in adults alters binocular circuit composition and impairs a depth-perception behaviour (visual cliff).
Overall, the data support a model in which astrocyte-secreted CCN1 coordinates maturational changes across several cell types to maintain the low-plasticity, stable state of adult sensory cortex — and conversely, reducing CCN1 can make adult cortex more permissive to remodelling.
Key Points
- Astrocyte Ccn1 expression increases from development into adulthood and falls after plasticity-inducing manipulations (dark rearing, monocular deprivation).
- Overexpressing CCN1 in juvenile visual cortex restricts experience-dependent remodelling; knocking out Ccn1 in adult astrocytes increases adult plasticity.
- CCN1 reduces excitatory drive onto layer 2/3 pyramidal neurons and enhances excitatory input to fast-spiking (PV) interneurons, promoting inhibitory maturation and PNN formation.
- CCN1 stimulates oligodendrocyte precursor differentiation and myelin-associated programmes in the visual cortex; adult astrocyte Ccn1 loss reduces local myelination.
- A D125A point mutation that prevents CCN1 binding to αVβ3/αVβ5 integrins abolishes CCN1’s effects on remodelling and aggrecan, implicating αV integrins in CCN1 signalling.
- Single-nucleus RNA-seq indicates CCN1 affects excitatory neurons and oligodendrocyte lineage cells most strongly, with transcriptional signatures linked to synaptic structure and myelination.
- Functionally relevant: adult Ccn1 conditional knockout mice show altered binocular circuit composition, reduced cell response reliability and impaired depth-perception behaviour (visual cliff).
- CCN1 acts as a multi-cell-type coordinator (neurons, astrocytes, oligodendrocytes, microglia) that enforces adult circuit stability; manipulating it offers a lever to modulate plasticity.
Why should I read this?
Short version: if you care about how adult brains stay ‘locked in’ — and how we might re-open that lock after injury — this paper gives you a concrete astrocyte-made culprit and a mechanism. It’s not just another synapse paper: CCN1 links astrocytes to neurons, myelination and extracellular matrices that together determine whether circuits stay stable or become plastic again. Read it if you want the experiments done for you — and a clear target to follow up.
Author style
Punchy: this work names a single, secreted astrocyte factor (CCN1) that actively maintains adult cortical stability across multiple cell types. If you work on plasticity, myelination, glia–neuron signalling or recovery after injury, the experimental depth here (transcriptomics, electrophysiology, in vivo calcium imaging, behaviour, snRNA-seq) makes this essential reading — the paper both identifies a mechanism and points to translational levers.
Context and relevance
Why it matters: decades of work have shown critical periods close as circuits mature; this paper shows the adult brain does not merely passively lose plasticity but requires ongoing astrocyte-derived cues to remain stable. That reframes astrocytes as active custodians of adult circuit identity. The findings link extracellular matrix/PNN biology, integrin signalling and oligodendrocyte maturation to a single astrocyte-secreted regulator, connecting several hot topics in systems and cellular neuroscience. Clinically, targeting CCN1 expression or its integrin interactions could be a strategy to enhance remodelling after stroke or injury while avoiding broad, uncontrolled plasticity.