Figure 2.

(A) Current models predict a soluble pool of Shank proteins at the post-synapse, as well as a post-synaptic density (PSD) bound pool recruited to the PSD by zinc binding. PSD bound Shank scaffolds proteins link receptors at the membrane to the actin cytoskeleton. Further, by binding with Neuroligin (Nlg) and Neurexin (Nrxn) complexes, the level of Shank3 at the PSD provides a transsynaptic signal to the pre-synapse to coordinate synaptic plasticity of both parts of the synapse. (B) Loss of Shank3 proteins at the synapse may destabilize synapses and prevent their maturation or formation. Heterozygous deletion or mutation of Shank3 in humans leaves one copy of the gene intact that produces proteins. (C) Increasing zinc levels by zinc supplementation might restore Shank3 levels by recruitment of Shank3 from the soluble synaptic pool to the PSD bound pool and might recruit additional Shank2 proteins. Strengthening the PSD scaffold in this way may compensate some deficits seen in forms of ASD caused by imbalance in the Nrxn-Nlg-Shank pathway.