Impact of transplanted juvenile human cortical neurons on plasticity of adult mouse cortical circuits

 Neural plasticity is greatest during development, but decreases into adulthood, and being able to reverse this timeline would have major implications for treating brain diseases. In some instances, such as transplantation of embryonic neurons in the adult brain, individual neurons recapitulate early development within a mature host. In these cases, plasticity of existing circuits appears to increase, but the underlying mechanisms remain unclear. Here I hypothesise that developing neurons impart their juvenile synaptic properties on mature networks, and thus explore heterochrony as a mechanism for plasticity induction. To address this, I will exploit species-differences in the timing of cortical neuron maturation, using a system where human pyramidal neurons are derived from embryonic stem cells and transplanted into the neonatal mouse cortex. Human neurons retain their protracted development, showing juvenile features for several months in an adult host. This will then be coupled with probing plasticity of the host visual cortex, using in vivo calcium imaging. Manipulating human neuron activity, transsynaptic tracing and single nucleus transcriptomics will be used to explore the underlying mechanisms. Neuronal plasticity is thought to be accelerated in neurodevelopmental disorders. Through xenotransplantation I can study plasticity of human neurons themselves, constituting a unique model to study neurodevelopmental diseases, and for developing neuron replacement therapies.