In a groundbreaking study published in Nature in 2025, researchers have unveiled a crucial role for astrocyte-derived CCN1 in maintaining the stability and function of binocular neural circuits in the adult visual cortex. This discovery sheds light on the molecular mechanisms that sustain sensory processing throughout adulthood and challenges longstanding assumptions that mature neural circuits are fixed and immutable.
The visual cortex’s ability to integrate information from both eyes to form coherent binocular vision relies on finely tuned neuronal circuits that respond selectively to input from either the contralateral or ipsilateral eye, or both. While previous work has characterized the developmental critical periods during which formative changes in ocular dominance occur, this study probes the persistence of plasticity and circuit maintenance mechanisms well into adulthood, focusing on the matricellular protein CCN1 expressed by astrocytes.
Using innovative longitudinal two-photon microscopy techniques, the team tracked calcium responses in layer 2/3 pyramidal neurons within the binocular zone of awake adult mice. By employing a genetic knockout of CCN1 specifically in astrocytes (Ccn1-cKO), they compared circuit responsiveness before and after monocular deprivation (MD), a classic paradigm for inducing ocular dominance plasticity. The results reveal that astrocyte CCN1 is necessary for maintaining the mature composition and balance of ipsilateral-, contralateral-, and binocularly responsive neurons.
Notably, prior to MD, Ccn1-cKO mice exhibited an anomalously high proportion of contralateral-responsive neurons, alongside a reduced population of binocularly responsive cells relative to wild-type controls. When subjected to five days of MD of the contralateral eye, knockouts experienced an increased turnover in binocular neurons and a substantial rise in unresponsive cells—a signature reminiscent of immature visual circuits. This striking phenotype underscores the role of CCN1 in preserving circuit maturation and stability into adulthood.
Ocular dominance index (ODI) analysis provided further insights. While wild-type animals exhibited the expected post-MD shift in ocular dominance favoring the non-deprived ipsilateral eye, such plasticity was absent in Ccn1-cKO mice. This suggests that the absence of CCN1 disrupts fundamental homeostatic adjustments within mature binocular circuits, preventing the adaptive rebalancing of eye-specific inputs following sensory perturbation.
Beyond cell-type proportions and ocular dominance shifts, the researchers uncovered altered functional properties within the visual circuitry of Ccn1-cKO mice. Contralateral-eye responsive neurons displayed distinct preferred orientations and poorer tuning fidelity compared to controls. Moreover, neuronal spiking correlations and response reliability during stimulus presentation were diminished, indicating compromised circuit coherence and information processing. Interestingly, these deficits did not extend to locomotion-modulated spiking, which remained intact.
To translate these circuit-level disruptions into behavioral consequences, the study employed the visual cliff assay, a sensitive test of depth perception rooted in binocular vision. Ccn1-cKO mice showed an impaired ability to discriminate the cliff from the safe zone, spending more time exploring the perilous edge and demonstrating increased zone transitions. These behavioral aberrations align with the circuit alterations observed and provide compelling evidence that astrocyte CCN1 not only modulates cellular physiology but also influences perceptual outcomes.
Molecularly, the team also examined perineuronal nets (PNNs), specialized extracellular matrix structures known to stabilize synaptic contacts and restrict plasticity. Labeling with Wisteria floribunda agglutinin (WFA) around parvalbumin-positive interneurons revealed a reduction in PNN density in Ccn1-cKO mice, particularly following MD. This suggests that CCN1 contributes to extracellular matrix remodeling, vital for sustaining circuit integrity and limiting plasticity beyond critical periods.
Collectively, these findings position astrocyte-secreted CCN1 as a pivotal factor that stabilizes mature binocular circuits, balances neuron responsiveness, and underlies adaptive plasticity in adult visual cortex. The work challenges the historical neuron-centric perspective and emphasizes astrocytic involvement in sensory processing maintenance.
This research opens exciting avenues for exploring astrocytic modulation in neuroplasticity and offers potential therapeutic angles for visual disorders where circuit instability or maladaptive plasticity contributes to deficits. Understanding how extracellular matrix components like CCN1 orchestrate synaptic configuration across lifespan stages may inform interventions aimed at restoring or preserving sensory function during aging or disease.
Future studies will need to investigate whether similar astrocyte-mediated mechanisms operate in other sensory and cognitive circuits and how CCN1 interacts with intracellular signaling pathways to effect synaptic stabilization. Additionally, delineating the temporal dynamics of CCN1 expression and its potential regulation by neuronal activity could reveal new targets for modulating plasticity in a controlled and context-dependent manner.
In summary, the astrocyte-derived matricellular protein CCN1 emerges as a critical stabilizer of adult binocular visual circuits, ensuring the maturation and homeostasis of eye-specific neuronal responses and enabling proper adaptive plasticity following sensory deprivation. This paradigm-shifting work highlights the intricacy of glial-neuronal crosstalk in maintaining functional brain architecture well beyond developmental periods.
Subject of Research:
Role of astrocyte-derived CCN1 in maintaining adult visual cortex binocular circuits and plasticity.
Article Title:
Astrocyte CCN1 stabilizes neural circuits in the adult brain.
Article References:
Sancho, L., Boisvert, M.M., Eddy, T. et al. Astrocyte CCN1 stabilizes neural circuits in the adult brain. Nature (2025). https://doi.org/10.1038/s41586-025-09770-w
DOI:
https://doi.org/10.1038/s41586-025-09770-w
Tags: adult visual cortexastrocyte function in neural stabilityastrocyte-derived CCN1binocular neural circuitsgenetic knockout studieslayer 2/3 pyramidal neuronsmaintenance of mature neural circuitsmolecular mechanisms of plasticitymonocular deprivation paradigmocular dominance plasticitysensory processing in adulthoodtwo-photon microscopy techniques
