Correcting excitatory-inhibitory imbalance in autism

  • Awarded: 2013
  • Award Type: Research
  • Award #: 274426

Autism appears to be caused by aberrant synapses, or connections between brain cells. A leading hypothesis is that a generalized hyper-excitability in the brains of individuals with autism impairs cognitive functions and increases seizure susceptibility.

However, it is difficult to examine how neural hyper-excitability contributes to autism traits and whether the inappropriate neural connectivity at its root can be corrected by balancing excitatory and inhibitory activity in the brain. One obstacle is that autism can be caused by a wide range of genetic mutations, making it difficult to model neural hyper-excitability.

In 2012, Benjamin Philpot and his team at the University of North Carolina at Chapel Hill found that genetic deletions of UBE3A create hyper-excitability in the brain due to differential modifications in excitatory and inhibitory synapses. UBE3A is known to be linked to some forms of autism.

The researchers plan to extend this work by examining the precise mechanisms by which dysregulation of UBE3A contributes to neural hyper-excitability and behavioral abnormalities. They plan to manipulate UBE3A levels in mice to determine the deficits that underlie neural hyper-excitability. Insights from this research may guide strategies for correcting the excitatory-inhibitory imbalance in UBE3A-linked and perhaps broader forms of autism.

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