Glucose-derived glutamate drives neuronal terminal differentiation in vitro

Neuronal maturation is the phase during which neurons acquire their final characteristics in terms of morphology, electrical activity, and metabolism. However, little is known about the metabolic pathways governing neuronal maturation. Here, we investigate the contribution of the main metabolic pathways, namely glucose, glutamine, and fatty acid oxidation, during the maturation of primary rat hippocampal neurons. Blunting glucose oxidation through the genetic and chemical inhibition of the mitochondrial pyruvate transporter reveals that this protein is critical for the production of glutamate, which is required for neuronal arborization, proper dendritic elongation, and spine formation. Glutamate supplementation in the early phase of differentiation restores morphological defects and synaptic function in mitochondrial pyruvate transporter-inhibited cells. Furthermore, the selective activation of metabotropic glutamate receptors restores the impairment of neuronal differentiation due to the reduced generation of glucose-derived glutamate and rescues synaptic local translation. Fatty acid oxidation does not impact neuronal maturation. Whereas glutamine metabolism is important for mitochondria, it is not for endogenous glutamate production. Our results provide insights into the role of glucose-derived glutamate as a key player in neuronal terminal differentiation. Synopsis Glucose oxidation sustains glutamate production and the terminal differentiation of neurons. Blunting glucose oxidation affects glutamate levels, neuronal maturation in terms of morphology and synaptic activity, and impairs protein synthesis. Genetic and chemical inhibition of the mitochondrial pyruvate transporter reduces glutamate levels, and impairs neuronal complexity, synaptogenesis, and synaptic transmission. The combination of a reduction in glutamate levels and altered mitochondrial function upon inhibition of glucose oxidation decreases the energy-demanding process of protein translation. The activation of group I metabotropic glutamate receptors rescues dendritic architecture, spine morphology defects, and restores local translation of synaptic proteins. Glucose oxidation sustains glutamate production and the terminal differentiation of neurons. Blunting glucose oxidation affects glutamate levels, neuronal maturation in terms of morphology and synaptic activity, and impairs protein synthesis.