Current genetic evidence links autism with defects in signaling between brain cells, or neurons, particularly at specialized regions of the neurons known as synapses. Bernardo Sabatini and his colleagues at Harvard Medical School plan to study how neuron activity affects synapse formation, focusing on the roles of three autism-associated proteins, which are members of the Shank, neurexin and neuregulin families.

To create a synapse, an extension from one neuron, known as a dendritic spine, makes contact with a nearby cell. Once the synapse is formed, electrical activation causes the release of neurotransmitter, inducing an electrical and chemical pulse in the dendritic spine of the receiving cell. Activity in both cells is necessary to stabilize the connection and strengthen the synapse. This process occurs both during normal development and during learning, but some evidence suggests it is impaired in autism. Dendritic spines are abnormal in mouse models of the disorder, as they are in models of related disorders, fragile X syndrome and tuberous sclerosis complex. Three of the known autism-associated genes, including members of the Shank, neurexin and neuregulin families, also produce proteins that are found in the synapse and that probably form a complex. Preliminary data from the Sabatini team suggest that, after neurotransmitter is detected in the spine, one of these Shank proteins travels out of the active dendritic spine. The protein’s role in the spine and why activity causes it to leave the spine remains unclear.

Sabatini and colleagues plan to study synapse formation in neurons deficient for these autism-associated genes, specifically looking for defects in the activity-dependent final steps. Using a combination of optics and chemistry, the researchers plan to carefully control the release of the neurotransmitter glutamate sensed by a dendritic spine. This technique will mimic the release of glutamate from the axon and trigger the electrochemical pulses that would normally be induced in the spine. The researchers then plan to look for changes in the number of synapses and in the morphology and composition of the dendritic spines. Based on their hypothesis that autism-related proteins assist in synapse formation, the researchers expect that loss of the proteins will cause consistent defects in these structures and in their signaling strength, which may underlie the learning and social impairments seen in people with autism.

As they learn more about this pathway, the researchers may also be able to uncover steps that could be manipulated to boost synaptic formation during development and learning, leading to new therapies for autism.