Copper is an endogenous modulator of neural circuit spontaneous activity

Significance Copper is traditionally regarded as a static, tightly bound cofactor in enzymes, but emerging data link more-loosely bound pools to cell signaling. Here we use molecular imaging to identify a role for copper in the brain as a modulator of spontaneous activity of developing neural circuits. First, we directly visualized a labile, loosely bound copper pool in hippocampal neurons and retinal tissue with a newly developed Copper Fluor-3 (CF3) indicator. We then used two-photon calcium imaging as readout of spontaneous activity to show that disruption of labile copper stores by acute chelation or genetic knockdown of the CTR1 (copper transporter 1) copper channel alters the frequency and spatial propagation of neural activity. The results establish the requirement for copper in a fundamental, dynamic property of brain circuitry.