A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells

Background:   The human brain is an intricate circuit of specialized neural cells. A disturbance in the homeostasis of this circuit can lead to various neuronal pathologies, including neurodevelopmental disorders. In such cases, the unavailability of affected human neurons for research has hampered the elucidation of disorder etiologies. Induced Pluripotent Stem Cells (iPSC) represent a rapidly evolving technology with great potential in areas ranging from basic research to drug discovery. When applied to neurodevelopmental disorders, the iPSC technology allows for the derivation of patient-specific neurons.

Objectives:   Here, we use iPSCs to model Rett Syndrome (RTT) in vitro, a neurodevelopmental condition under the umbrella of the Autism Spectrum Disorders.

Methods:  N/A

Results: The comparison of human RTT and non-affected neurons has generated insights into the molecular and cellular mechanism of the disease, such as a deficit in synaptogenesis. Moreover, we used new techniques to measure neuronal network connectivity of iPSC-derived neurons in a dish. Our data display a network connectivity deficit and excitatory/inhibitory neurons imbalance in RTT neuronal cultures, compared to controls. Interestingly, most of these phenotypes can be rescued by the use of IGF-1, a molecule currently in clinical trial to RTT.  

Conclusions:  Our work with iPSC-derived cells suggests that therapeutic interventions using IGF-1 may be beneficial for RTT and possibly other neurodevelopmental disorders with similar phenotypes.