Genetic mechanisms of human neuronal development and connectivity, in link with evolution and neurodevelopmental diseases.

Neuronal development in the human cerebral cortex is considerably prolonged compared to that of other mammals. It results in extended critical periods of learning and plasticity that have been proposed to play a role in the acquisition of human-specific cognitive features. In mammals, the rate of embryonic development is correlated to the resting metabolic rate as assessed by oxygen consumption. Within the cell, mitochondria are the site of oxidative phosphorylation. Mitochondria have also been linked to neuronal development and plasticity, in particular to the morphology of dendrites, spines and synapses. We explored whether mitochondria influence the species-specific timing of cortical neuron maturation. During cortical neuron maturation, we documented a progressive increase of mitochondrial size, quantity and activity. By comparing human and mouse cortical neuronal maturation at high temporal and cell resolution, we found a slower mitochondria development in human cortical neurons compared with that in the mouse, together with lower mitochondria metabolic activity, particularly that of oxidative phosphorylation. Stimulation of mitochondria metabolism in human neurons resulted in accelerated development in vitro and in vivo, leading to maturation of cells weeks ahead of time, whereas its inhibition in mouse neurons led to decreased rates of maturation. Mitochondria are thus important regulators of the pace of neuronal development underlying human-specific brain neoteny.