Coordinated control of synapse development by autism-linked genes

  • Awarded: 2011
  • Award Type: Research
  • Award #: 206919

The development of brain cell connections, or synapses, occurs during the third trimester of gestation and throughout the first few years of life. Proper synaptic formation and brain wiring require a complex interaction between brain activity, usually driven by sensory experience, and genes.

Many of the genes whose mutations are linked to autism play a role in synapse formation or elimination (pruning) during brain development. Synaptic pruning is a normal developmental process that results in the elimination of inappropriate or unused synapses. Some people with autism show an excess of synapses, consistent with a deficit in synaptic pruning.

Kimberly Huber and her colleague Christopher Cowan at the University of Texas Southwestern Medical Center in Dallas have identified several genes that are required for proper synaptic pruning in the normal brain and that have links to autism. In response to brain activity, the transcription factor MEF2 triggers activation of a number of genes that lead to synapse elimination.

The researchers also found that the gene linked to fragile X syndrome, FMR1, is required for MEF2 to cause pruning1. FMR1 is a well-known autism risk gene that plays a role in converting MEF2-activated genes into proteins. MEF2 activates protocadherin 10 (PCDH10), another gene whose deletion is associated with autism.

Huber’s team found that PCDH10 is regulated by FMR1 and is required for synaptic pruning. Furthermore, MEF2 induces synapse elimination through degradation of the postsynaptic scaffolding protein PSD-952. These results implicate multiple autism-linked genes in a synapse elimination process and suggest that deficits in activity- and experience-dependent synaptic pruning may be common in autism.

These findings motivate future work to understand the role of other autism-linked genes in synapse elimination, and how a deficit in experience-dependent pruning contributes to autism. Understanding the synaptic pruning process may allow researchers to better understand how experience modifies the brain differently in autism. It may also lead to the identification of new therapeutic targets and treatments for the disorder.

 

References

1.Pfeiffer B.E. et al. Neuron 66, 191-197 (2010) PubMed
2.Tsai N.P. et al. Cell 151, 1581-1594 (2012) PubMed
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