Metabolic differences in hippocampal 'Rett' neurons revealed by ATP imaging

Understanding metabolic control of neuronal function requires detailed knowledge of ATP handling in living neurons. We imaged ATP in organotypic hippocampal slices using genetically encoded sensor Ateam 1.03 modified to selectively transduce neurons in the tissue. ATP imaging indicated distinct differences in ATP production and consumption in dentate gyrus and cornu ammonis (CA) areas. Removal of extracellular Mg2 + from the bath evoked epileptiform-like activity that was accompanied by ATP decline from 2-3 to 1-2 mM. The slices fully recovered from treatment and showed persistent spontaneous activity. Neuronal discharges were followed by transient ATP changes and periodic activation of ATP-sensitive K+ (K-ATP) channels. The biggest ATP decreases during epileptiform-like episodes of activity were observed in CA1 and CA3 neurons. Examination of neurons from the Rett model mice MeCP2−/y showed that seizure-like activity had earlier onset and subsequent spontaneous activity demonstrated more frequent discharges. Hippocampal MeCP2−/y neurons had higher resting ATP levels and showed bigger ATP decreases during epileptiform-like activity. More intense ATP turnover in MeCP2−/y neurons may result from necessity to maintain hippocampal function in Rett syndrome. Elevated ATP may make, in turn, Rett hippocampus more prone to epilepsy due to inadequate activity of K-ATP channels.