Neuronal circuit dissection and novel therapeutic strategies in neurodevelopmental disorders

Summary

Date: 
October 28, 2014 - 1:00pm
Location: 
NW 243
About the Speaker
Name: 
Michela Fagiolini (Children's Hospital)

Activity-dependent neuronal circuit refinement critically contributes to Rett Syndrome (RTT), a neurodevelopmental disorder caused by de novo mutations of methyl-CpG-binding protein, MECP2. The nature of the synaptic abnormality and how it explains the clinical course of RTT is, however, still largely unknown. Moreover, there is no drug treatment available to prevent loss or allow recovery of cortical function in RTT patients. To this end, we have recently discovered a clear regression of visual function in mouse models of RTT and demonstrated its rescue by genetic manipulation of NMDA receptor (R) subunit composition. Studies conducted in postmortem brain tissue of RTT patients first identified abnormalities in the excitatory glutamate NMDAR, with cortex NMDAR expression increased in early life but decreases below normal levels after age 10. These findings raise the possibility that administration of NMDAR modulators may delay or allow recovery of cortical function in RTT.  This hypothesis is testable and should be performed in a preclinical animal setting first and then rapidly translated to clinical trial. The identification of a specific receptor pathway upon a particular cortical circuit offers an accessible membrane target for drug intervention strategies that do not rely on the global re-expression of Mecp2 itself.