Microglia regulate developmental transitions in synaptic plasticity rules in the medial prefrontal cortex

Synaptic plasticity is governed by rules that determine how patterns of neural activity are converted into changes in synaptic weights. While neocortical plasticity rules appear to shift from Hebbian to three-factor forms during development, the cellular mechanisms underlying this transition remain unclear. Here, we show that microglia mediate the developmental transition of plasticity rules at individual dendritic spines in the medial prefrontal cortex (mPFC) during juvenile-to-adolescent maturation. After maturation, microglia suppressed Hebbian activity–induced spine enlargement via a humoral factor. This suppression was relieved by noradrenaline through microglia-intrinsic cAMP signaling, thereby enabling a three-factor rule for gating plasticity. The adolescent mPFC required three-factor plasticity signaling for the acquisition of socially learned fear. Local microglial ablation enhanced learning efficiency but also altered pain sensitivity in a learning-dependent manner, suggesting that microglial suppression safeguards pre-existing emotional circuits. Together, these findings identify microglia as critical regulators of developmental plasticity-rule transitions in the mPFC.