Astrocytic Ca²⁺ prevents synaptic depotentiation by limiting repetitive activity in dendrites during motor learning
Publication date: 13/10/2025
Authors: Lai B, Yuan D, Xu Z, Zhang F, Li M, Martín-Ávila A, Chen X, Chen K, Ouyang K, Yang G, Chao MV, Gan WB
Journal: Nature Neuroscience
Commentary: This study investigates the role of astrocytic Ca²⁺ signaling in learning-related synaptic plasticity in the living brain, focusing on motor learning in the mouse motor cortex. While astrocytic Ca²⁺ has been shown to modulate synaptic plasticity in vitro, its function during learning in vivo has remained unclear. The authors demonstrate that motor training induces synaptic potentiation on apical dendrites of layer 5 pyramidal neurons, accompanied by widespread increases in astrocytic Ca²⁺ activity. Importantly, reducing astrocytic Ca²⁺—through genetic, pharmacological, or chemogenetic manipulations—led to synaptic depotentiation during training and impaired motor performance improvement. Synaptic weakening occurred selectively on dendrites exhibiting repetitive dendritic Ca²⁺ spikes. On these dendrites, previously active spines underwent CaMKII-dependent size reduction, suggesting a mechanism for activity-dependent synaptic depotentiation. The study further shows that astrocyte-derived ATP, converted to adenosine, suppresses excessive dendritic Ca²⁺ activity via adenosine receptor activation, thereby preventing synaptic weakening. This identifies astrocytic Ca²⁺ as a key regulator that limits repetitive dendritic activity during learning. In contrast, dendrites with less repetitive Ca²⁺ activity showed synaptic potentiation, which was enhanced by intact astrocytic Ca²⁺ signaling, indicating a dual role for astrocytes in both preventing synaptic weakening and promoting strengthening. The findings highlight the importance of the GPCR–IP3R2 signaling pathway in astrocytic Ca²⁺ dynamics. Finally, the observation that motor training elevates astrocytic Ca²⁺ across multiple brain regions suggests that similar astrocyte-dependent mechanisms may broadly contribute to learning-related synaptic plasticity.
Commented by: Federica Campanelli
DOI: https://doi.org/10.1038/s41593-025-02072-4
