Garcia-Rodriguez, D.; Yunta-Sanchez, S.; Antequera-Duwel, M.; Hidalgo-Lopez, L.; Agulla, J.; Sancha-Ortega, L.; Lapresa, R.; Fernandez, E.; Martinez-Gallego, I.; Sanchez-Gallego, A.; Fernandez-Garcia, J.; Plaza-Garcia, S.; Keren, I.; Chattopadhyay, M.; Eaton, S.; Heales, S. J. R.; Rodriguez-Moreno, A.; Planque, M.; Fendt, S.-M.; Ramos-Cabrer, P.; Aldana, B. I.; Almeida, A.; Jimenez-Blasco, D.; Bolanos, J. P.

Astrocytes are glycolytic cells that convert a substantial fraction of glucose-derived pyruvate into lactate, a metabolite implicated in supporting neuronal energy demand and modulating excitability, plasticity and memory. This view has placed astrocytic lactate production and export at the centre of astrocyte-neuron metabolic coupling, but whether mitochondrial pyruvate utilization in astrocytes is dispensable in vivo or fulfils an essential function in the intact brain remains unknown. Here we show that adult astrocyte-specific deletion of Mpc2, encoding an obligatory mitochondrial pyruvate carrier subunit, causes motor deficits, neuronal hyperexcitability and seizure-associated lethality. Metabolic profiling revealed pyruvate diversion toward alanine as an unsuccessful compensatory bypass, together with impaired tricarboxylic acid-cycle metabolism and an imbalance in neurotransmitter-related pools, including glutamate, glutamine and {gamma}-aminobutyric acid. Thus, astrocytic mitochondrial pyruvate import is not primarily required for bioenergetic purposes but acts as a non-redundant anaplerotic gate that maintains neurotransmitter homeostasis, excitation-inhibition balance and seizure resistance in vivo.