Reversible cyclosporin A-sensitive mitochondrial depolarization occurs within minutes of stroke onset in mouse somatosensory cortex in vivo: a two-photon imaging study.

Neuronal structure and function are rapidly damaged during global ischemia but can in part recover during reperfusion. Despite apparent recovery in the hours/days following an ischemic episode, delayed cell death can be initiated, making it important to understand how initial ischemic events affect potential mediators of apoptosis. Mitochondrial dysfunction and the opening of the mitochondrial permeability transition pore (mPTP) are proposed to link ischemic ionic imbalance to mitochondrially mediated cell death pathways. Using two-photon microscopy, we monitored mitochondrial transmembrane potential (Deltapsi(m)) in vivo within the somatosensory cortex during ischemia and reperfusion in a mouse global ischemia model. Our results indicated a synchronous loss of Deltapsi(m) within 1-3 min of ischemic onset that was linked to within seconds of plasma membrane potential (Deltapsi(p)) depolarization. Deltapsi(m) recovered rapidly upon reperfusion, and no delayed depolarization was observed over 2 h. Cyclosporin A treatment largely blocked Deltapsi(m) collapse during ischemia, suggesting a role for the mPTP. Blocking Deltapsi(m) depolarization did not affect structural damage to dendrites, indicating that the opening of the mPTP and damage to dendrites are separable pathways that are activated during Deltapsi(p) depolarization. Our findings using in vivo imaging suggest that mitochondrial dysfunction and specifically the activation of the mPTP are early reversible events during brain ischemia that could trigger delayed cell death.