Accumulating evidence suggests that autism spectrum disorder symptoms arise from a disruption in the process of experience-dependent synaptic plasticity that normally occurs during critical periods of development. Critical periods are windows of time when appropriate sensory, motor and cognitive function are essential for the refinement and tuning up of brain circuits. Rett syndrome is recognized as one of the clearest genetic examples of autism, and is caused by mutations in the MeCP2 gene.
Studies suggest that MeCP2 controls expression of other genes crucial for maturation of brain circuits during these critical periods, and that individuals with Rett syndrome may suffer from alterations in synaptic plasticity. Carla Shatz and her colleagues at Stanford University discovered that a family of molecules — major histocompatibility class I (MHCI), well known for their function in the immune system — are also crucial for regulating synaptic plasticity during critical periods.
Shatz and her group proposed that MHCI expression at synapses may be a common mechanism for how both genes and environment can alter brain circuit tuning during development. Using a strain of mice with a mutation in the MeCP2 gene, preliminary data show that plasticity during a critical period of visual cortex development is defective and that levels of MHCI proteins are elevated.
The researchers aimed to reverse the defective cortical plasticity in these mice by infusing a pharmacological inhibitor of MHCI signaling. The inhibitor worked well in normal mice, not only enhancing cortical plasticity and generating new synapses, but also restoring vision in a mouse model of the vision disorder amblyopia. However, the same treatment had no effect when used in Rett model mice. These observations are consistent with the idea that MeCP2 is needed for activity-dependent synapse strengthening, but not for activity-dependent synapse weakening or pruning. Treatments that prevent pruning may not lead to restoration of plasticity and function in Rett syndrome in the absence of MeCP2.