A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

The formation of memories is believed to depend on the strengthening of connections, called synapses, between neurons in the brain. When neurons are activated together, their synaptic connections become permanently strengthened to record the memory. This strengthening is called activity-dependent long-term potentiation. As long-term potentiation develops, more protein receptors are added to the receiving side of the synapse. This allows the receiving neuron to produce a larger electrical response to the signaling chemicals it receives from the neuron on the sending side of the synapse. The addition of receptors is regulated by a set of enzymes held near the membrane of the synapse by a protein scaffold known as the postsynaptic density. A major scaffold protein called PSD-95 contains binding sites, known as PDZ domains, that hold protein receptors and regulatory enzymes in place. One regulatory enzyme called synGAP is present in large numbers in the postsynaptic density and binds to the same PDZ domains as the receptors. Humans that have just one copy (instead of the usual two) of the gene that encodes synGAP have cognitive disabilities that are often accompanied by autism and epilepsy. By studying purified proteins, Walkup et al. found that adding phosphate groups to synGAP reduces the enzyme’s ability to bind to the PDZ domains. This reduced binding ability could make more PDZ domains available to bind to protein receptors and hold them at the synapse. To measure the effect of reduced synGAP levels on the proteins found at postsynaptic densities, Walkup et al. used mice that had just one copy of the synGAP gene in their neurons. These mice have less synGAP in their postsynaptic densities and more of three proteins that bind to PDZ domains. These proteins hold receptors in the synapse and help synapses to form. Thus, synGAP may restrict the binding of other proteins to the PDZ domains in order to regulate the strength of the synapse. Further experiments are now needed to investigate the importance of restriction by synGAP of binding to PDZ domains under a variety of circumstances in which the activity of neurons alters the strength of synapses.