In:
Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6632 ( 2023-02-10)
Abstract:
During embryonic development, the temporal sequence of events is usually conserved throughout evolution, but it can occur at very different time scales depending on the species or cell type considered. The human cerebral cortex is characterized by a considerably prolonged timing of neuronal development compared with other species, taking months to years to reach maturity compared with only a few weeks in the mouse. The resulting neoteny is thought to be a key mechanism enabling enhanced function and plasticity of the human brain. Human and nonhuman cortical neurons cultured in vitro or xenotransplanted into the mouse brain develop along their species-specific timeline. This suggests that species-specific developmental timing is controlled by cell-intrinsic mechanisms, but these remain essentially unknown. RATIONALE Metabolism and mitochondria are key drivers of cell fate transitions in many systems, including the developing brain. Here, we tested whether they could be involved in the species-specific tempo of cortical neuron development and human brain neoteny. We developed a system of genetic birth-dating to label newly born neurons with high temporal and cellular resolution, and directly compared the development of human and mouse cortical neurons over time. We thus profiled, across time and species, mitochondria morphology, gene expression, oxygen consumption, and glucose metabolism. Next, we used pharmacological or genetic manipulation of human or mouse neurons to enhance or decrease their mitochondria function, and determined the consequences on the speed of neuronal development. RESULTS We found that mitochondria are initally low in size and quantity in newborn neurons, and then grow gradually as neurons undergo maturation following a species-specific timeline. Whereas in mouse neurons, mitochondria reach mature patterns in 3 to 4 weeks, they only do so after several months in human neurons. We next measured mitochondria oxidative activity and glucose metabolism in human and mouse developing cortical neurons. This revealed a species-specific timeline of functional maturation of mitochondria, with mouse neurons displaying a much faster increase in mitochondria-dependent oxidative activity than human neurons. We also found that human cortical neurons displayed lower levels of mitochondria-driven glucose metabolism than did mouse neurons at the same age. Finally, we tested whether mitochondria function affects neuronal developmental timing. We performed pharmacological or genetic manipulation of human developing cortical neurons to enhance mitochondria oxidative metabolism. This led to accelerated neuronal maturation, with neurons exhibiting more mature features weeks ahead of time, including complex morphology, increased electrical excitability, and functional synapse formation. Similar treatments on mouse neurons also led to faster maturation, whereas inhibition of mitochondria metabolism in mouse neurons led to a decrease in developmental rates. CONCLUSION Our work identifies a species-specific temporal pattern of mitochondria and metabolic development that sets the tempo of neuronal maturation. Accelerated human neuronal maturation using metabolic manipulation might benefit pluripotent stem cell–based modeling of neural diseases, which remains greatly hindered by protracted neuron development. Tools to accelerate or decelerate neuronal development could allow testing of the impact of neuronal neoteny on brain function, plasticity, and disease. Mitochondria metabolism sets the tempo of neuronal development. Mitochondria dynamics and metabolism display species-specific timelines during cortical neuron development. In newborn neurons, mitochondria are small in number and metabolic activity, and then increase gradually during neuronal maturation. Enhanced mitochondria metabolism in human neurons leads to accelerated maturation, including increased neurite complexity, excitability, and synaptic function. Decreased mitochondria metabolism in mouse neurons leads to decelerated neuronal maturation.
Type of Medium:
Online Resource
ISSN:
0036-8075
,
1095-9203
DOI:
10.1126/science.abn4705
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2023
detail.hit.zdb_id:
128410-1
detail.hit.zdb_id:
2066996-3
detail.hit.zdb_id:
2060783-0
SSG:
11
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