A chimeric mouse model to study human iPSC-derived neurons: the case of a truncating SHANK3 mutation

Area of Science:

• Neuroscience
• Developmental Biology
• Stem Cell Research

Background:

• Autism spectrum disorders (ASD) involve neonatal developmental events.
• Human induced pluripotent stem cells (iPSC) enable studying these events.
• SHANK3 mutations are linked to ASD and affect neuronal spinogenesis in vitro.

Purpose of the Study:

• To analyze the in vivo integration and maturation of human iPSC-derived neurons in a mouse model.
• To investigate the effects of SHANK3 mutations on neuronal development in vivo.
• To establish humanized chimeric mouse models for studying ASD-associated mutations.

Main Methods:

• Transplantation of human iPSC-derived neuronal precursor cells (NPC) into newborn mouse cortex.
• Co-transplantation of control and patient-derived NPC.
• Analysis of neuronal integration, maturation, cell soma size, axonal projections, and spinogenesis at different time points.

Main Results:

• Transplanted human neurons integrated and projected axons in the adult mouse brain.
• A reduction in cell soma size and axonal projections was observed at 30 days post-transplantation in patient-derived neurons.
• No alterations in spinogenesis were detected at this early developmental stage in vivo, contrasting with in vitro findings.

Conclusions:

• Humanized chimeric mouse models provide a platform for in vivo analysis of ASD-associated mutations.
• Early in vivo development of SHANK3-mutated neurons shows distinct phenotypes compared to in vitro.
• This model allows for visualization of ASD-related phenotypes in a complex biological system.