Development and Wiring of Cortical Neurons: Implications for Autism Spectrum Disorders

Summary

Date: 
February 4, 2015 - 1:00pm
Location: 
NW 243
About the Speaker
Name: 
Jessica MacDonald (Macklis Lab)

The neocortex contains hundreds of distinct subtypes of precisely connected neurons, allowing it to perform remarkably complex tasks of high-level cognition. Callosal projection neurons (CPN) connect the cerebral hemispheres via the corpus callosum, integrating cortical information, and playing key roles in associative cognition. Disruptions in CPN development have been implicated in a number of neurodevelopmental disorders, including the autism spectrum disorder Rett Syndrome (RTT). We have identified novel molecular controls over CPN development, including a transcriptional co-regulator, Cited2, that regulates two distinct stages of CPN development. In addition, we focused on CPN to investigate molecular disruptions underlying RTT, caused by mutations in the transcriptional regulator MeCP2. We identified aberrant NF-κB signaling in Mecp2-null CPN, and demonstrate that genetic attenuation of this pathway can rescue RTT phenotypes. Further, we investigated potential therapeutic treatment of Mecp2-null mice by dietary supplementation with the NF-κB inhibitor vitamin D, and identified dose-dependent amelioration of CPN dendritic complexity and reduced soma size phenotypes. These results provide new insight into both the fundamental neurobiology of RTT, and potential therapeutic strategies via NF-κB pathway modulation.