Controlling the timing of human cortical neuron development: from upstream mechanisms to impact on circuit plasticity.

Human brain development is characterized by a prolonged timing of maturation of cortical neurons compared with other species.

The resulting ‘neoteny’ may constitute a key evolutionary mechanism enabling the exceptional gain of complexity of human brains compared to other animals.

However the molecular mechanisms underlying human neuronal neoteny, and its impact on circuit function, are largely unknown.

We previously discovered that human cortical neurons transplanted in the mouse cortex develop along their species-specific timeline, pointing to cell-intrinsic mechanisms as major players in the timing of neuronal development.

We also recently found that mitochondria dynamics and function regulate neurogenesis through direct impact on chromatin remodeling, and that they display striking species-specific differences during cortical neuron maturation.

These data lead us to propose that mitochondria and metabolism act as key species-specific modifiers on the timing of cortical neuron maturation, through epigenetic effects on the underlying gene regulatory network, ultimately leading to human neural neoteny.

To test this radical hypothesis we will identify which molecular features of mitochondria and metabolism differ during cortical neuron maturation of mouse, macaque and human species.

Then we will test the impact of the species-specific molecular features on neuronal maturation timing, using an innovative screening platform for human cortical neuron maturation. Factors that accelerate neuronal maturation will be studied by focusing on their effect on chromatin remodeling.

Finally we will determine the impact of manipulating neuronal maturation timing at the circuit level, using a new model of in vivo human neuron plasticity.

This project will shed new light on how developmental timing uniquely controls human brain structure and function, with far-reaching implications for our understanding of neural evolution, plasticity and disease.