In a recent study the mystery as to why kids with Rett syndrome start out their lives normally during infancy and then become progressively abnormal at 12 to 18 months of age. The new research from Children's Hospital Boston studied synapse development in mice with a mutation in the Mecp2 gene, the same gene linked to human Rett syndrome. Researchers found strong evidence that the loss of functioning Mecp2 prevents synapses and circuits from maturing and refining in response to cues from the environment - just at the time when babies' brains should be maximally receptive to these cues.
Chen believes her findings may have implications not just for Rett syndrome, but for other autism spectrum disorders.
"Many ASDs manifest between 1 and 2 years of age, a period when kids are interacting more with the outside world," Chen said.
"The brain of an autistic child looks normal, but there's a subtle difference in connections that has to do with how they process experiences.
"If you could diagnose early enough, there might be a way to alter the course of the disease by modifying experience, such as through intense one-to-one therapy," she stated.
Chen and colleagues focused on a synaptic circuit in the brain's visual system that is relatively easy to study, known as the retinogeniculate synapse.
It connects the cells receiving input from the eye to the lateral geniculate nucleus, an important relay station in the brain's thalamus. Visual input from the outside world, during a specific "critical period", is crucial for its normal development.
The team tested the functioning of the circuit by stimulating the optic tract and measuring electrical responses in the thalamus to see how the neurons were connected, and how strong the connections were.
In Mecp2-mutant mice, these recordings indicated that the visual circuit formed normally at first, and that during the second week of life, weaker connections were pruned away and others strengthened, just as they should be.
But after day 21 of life - after mice open their eyes and when the visual circuitry should be further pruned and strengthened based on visual experience - it became abnormal.
The number of inputs and connections actually increased, while the strength of the synapses decreased.
This pattern was similar to that seen when normal mice were kept in the dark after day 21, depriving them of visual stimulation.
Together, the findings suggest that Mecp2 is critically important to our ability to refine synaptic circuits based on sensory experience. Without Mecp2, the circuit fails to incorporate this experience.
"During this last phase of development, you need sensory input to lock down and stabilize the connections," Chen explained.
"But the circuit is not getting the right signal to stabilize, and continues to look around for the right connections," she said.
In patients with Rett syndrome, the reduction in Mecp2 levels is especially striking in the thalamus, which processes and relays sensory information to the cortex, where thought, memory and language reside.
"It's very telling that we see these synaptic abnormalities in the thalamus, which is like a switchboard operator for the brain. A small disruption in the thalamus can radiate to large areas of the cortex," Chen explained.
This model of Rett syndrome is consistent with mouse models of other autism-related disorders like Fragile X and Angelman syndrome, which also show abnormalities during experience-dependent maturation of circuits.
"There could be a problem with how information is taken in. What's being perceived is different, so the response is different," Chen added.
Chen and colleagues are now investigating whether reactivating Mecp2 at different times could improve organization of the visual circuitry.
The findings have been published in the April 14 issue of Neuron.