Neuronal activity induces aggrecan expression to drive perineuronal net formation in cortical neurons

Synaptic plasticity, driven by activity-dependent changes in neuronal connectivity, underlies learning and memory. However, the mechanisms that sustain long-term synaptic stabilization are not well understood. Perineuronal nets (PNNs), which are lattice-like extracellular matrix structures that enwrap neurons, are thought to stabilize synapses. However, the mechanisms regulating their formation remain unclear. Here, we found that neuronal activity induces transcription of aggrecan, a core PNN component, which in turn promotes PNN assembly. In primary cultured mouse cortical neurons, pharmacological stimulation of neuronal activity robustly increased aggrecan expression, whereas activity blockade suppressed it. Among the PNN-related genes examined, aggrecan alone exhibited strong activity-dependent transcriptional regulation. Analysis of published in vivo datasets revealed selective upregulation of aggrecan in parvalbumin-positive interneurons following sensory stimulation. This regulation required calcium influx through voltage-gated calcium channels and was dependent on cAMP response element binding protein (CREB) signaling and chromatin remodeling. These findings reveal a novel molecular link between neuronal activity and PNN formation, providing insights into the mechanisms underlying the long-term stabilization of neural circuits.