Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1

Rachel S. White, Anup K. Bhattacharya, Yong Chen, Madeleine Byrd, Mary F. McMullen, Steven J. Siegel, Gregory C. Carlson, Sangwon F. Kim

Activation of NMDA receptors can induce iron movement into neurons by the small GTPase Dexras1 via the divalent metal transporter 1 (DMT1). This pathway under pathological conditions such as NMDA excitotoxicity contributes to metal-catalyzed reactive oxygen species (ROS) generation and neuronal cell death, and yet its physiological role is not well understood. We found that genetic and pharmacological ablation of this neuronal iron pathway in the mice increased glutamatergic transmission. Voltage sensitive dye imaging of hippocampal slices and whole-cell patch clamping of synaptic currents, indicated that the increase in excitability was due to synaptic modification of NMDA receptor activity via modulation of the PKC/Src/NR2A pathway. Moreover, we identified that lysosomal iron serves as a main source for intracellular iron signaling modulating glutamatergic excitability. Our data indicates that intracellular iron is dynamically regulated in the neurons and robustly modulate synaptic excitability under physiological condition. Since NMDA receptors play a central role in synaptic neurophysiology, plasticity, neuronal homeostasis, neurodevelopment as well as in the neurobiology of many diseases, endogenous iron is therefore likely to have functional relevance to each of these areas.