Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits

Abstract

How neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here we investigate human cortical neuron development, plasticity and function, using a mouse/human chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging revealed that the human neurons develop morphologically and functionally following a prolonged developmental timeline, revealing the cell-intrinsic retention of juvenile properties of cortical neurons as an important mechanism underlying human brain neoteny. Following maturation, human neurons transplanted in the visual cortex display tuned responses to visual stimuli that are similar to those of mouse neurons, indicating capacity for physiological synaptic integration of human neurons in mouse cortical circuits. These findings provide new insights into human neuronal development, and open novel experimental avenues for the study of human neuronal function and diseases.

Species-specific pace of development is associated with differences in protein stability

“…Having identified a global scaling factor for the GRN, we investigated the mechanism that sets the timescale. We reasoned that the mechanism was likely to be cell-autonomous since the temporal differences are observed between mouse and human cells grown in vitro, and it has been shown that in vitro differentiated cells transplanted to a host follow their own species-specific dynamics (30)(31)(32). Since the directed differentiation towards MNs occurs in response to Shh signalling, we hypothesized that the delay in the GRN in human compared to mouse could be a consequence of a reduced sensitivity to signalling.…”

Genetic developmental timing revealed by inter-species transplantations in fish

“…Besides the vast literature on inter-species transplantations, the topic of developmental timing was barely approached. A recent example involves transplanting ESC-derived cortical cells to assess the dynamics of neuronal differentiation, using human cortical neurons (where maturation takes months to years) transplanted into mice (where maturation takes a few weeks) (Linaro et al, 2019). The authors report that transplanted human neurons go through an extended maturation period compared to their mice counterpart, retaining juvenile properties even when the host mice was already an adult.…”

Cerebral organoids as tools to identify the developmental roots of autism

“…Intrinsic properties improved over time; membrane potential hyperpolarization, increase in maximum sodium currents, increased firing rates, dendritic length, and dendritic spine density. Two-photon and calcium imaging experiments found an increase in calcium activity in human neurons during mouse visual stimulation indicating synaptic integration within the host cortex [85].…”