Downregulation of calcium-activated potassium channels drives cortical excitability dysfunction in a model of Itgb3-associated autism

Layer V pyramidal neurons, particularly pyramidal tract (PT) neurons, are essential for cortical output. Genetic studies have linked ITGB3, the gene encoding the cell-adhesion molecule β3 integrin, to autism spectrum disorder (ASD), yet its role in brain function remains poorly understood. Here, we investigate β3 integrin function in the prefrontal cortex, revealing its selective regulation of PT neuron excitability. β3 integrin modulates action potential (AP) discharge through its interaction with Ca2+-activated SK2 channels. Genetic ablation of Itgb3 reduces SK2 channel surface expression, impairing the gain, adaptation and precision of AP discharge in PT neurons. Phosphoproteomic analysis reveals altered protein kinase A (PKA)-dependent phosphorylation of Tau in Itgb3 KO mice, while PKA inhibition restores SK2 channel currents, linking phosphorylation changes to excitability defects. These findings identify a novel β3 integrin-dependent signaling pathway as a selective key modulator of PT neuron function, and provide insight into the cellular mechanisms linking dysfunction in cortical output to ASD.