Mechanisms of synapse elimination by autism-linked genes

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

The development of brain cell connections, or synapses, in humans occurs during the third trimester of prenatal life and throughout the first few years of life. Proper synaptic formation and brain wiring requires 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 pruning during brain development. Some people with autism show an excess of synapses, consistent with a deficit in synaptic pruning. Synaptic pruning is a normal developmental process that results in the elimination of inappropriate or unused synapses.

Kim Huber and her colleague Chris Cowan 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, 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 pruning. FMR1 is a well-known autism risk gene that plays a role in converting MEF2-activated genes into proteins. MEF2 activates protocadherin 10, or PCDH10, whose deletion is associated with autism. Huber’s team has found that PCDH10 is regulated by FMR1 and is required for synaptic pruning.

The researchers hypothesize that a deficit in MEF2-mediated pruning contributes to autism. They plan to test whether the brains of mice lacking MEF2 have more synapses than normal, as observed in individuals with autism. They also plan to assess autism-related behaviors in these mice.

Subscribe to our newsletter and receive SFARI funding announcements and news