Most of the genes known to be associated with autism seem to regulate how neurons communicate with each other at structures called synapses. Li-Huei Tsai and her colleagues at the Massachusetts Institute of Technology study the role of CDK5, an enzyme involved in synapse activity, and its influence on SHANK3, another protein known to be important in autism.
Located at the junction of two neurons, synapses are signaling complexes that send neurotransmitters and other molecules from one cell to another. If enough signaling molecules are released and detected at the synapse, the receiving neuron becomes activated. Throughout life, multiple activations can improve a synaptic connection, such as during learning.
Mutations in genes associated with autism appear to disrupt synapse formation, which may account for the social and language impairments as well as the mental retardation often associated with the disorder. In mice, neurons lacking CDK5 show a weaker electrophysiological response after an activating signal, leading to fewer synapses and impaired learning compared with controls.
Tsai and her colleagues have shown that CDK5 adds a phosphate group, a process known as phosphorylation, to the synaptic protein SHANK3. CDK5 also phosphorylates other proteins at the synapse, such as the N-type calcium channel CaV2.2. The researchers investigated whether CDK5, SHANK3, CaV2.2 and other proteins participate in a pathway that controls the creation of synapses. If so, this pathway may be disrupted in autism.
They found that, for proper neuron activity, CDK5 must phosphorylate both SHANK3 and CaV2.2 at the synapse. Therefore, a therapeutic drug affecting one of these synaptic targets of CDK5 may improve neurological functioning in people with autism.
