The postsynaptic density (PSD) is a cytoskeletal specialization that is located beneath the postsynaptic membrane and directly contiguous with the presyn-aptic “active zone” of excitatory synapses. Glutamate receptors, synaptic proteins, scaffolding proteins, kinases, and other downstream-signaling proteins are located within this PSD. There are several scaffolding proteins within the PSD including membrane-associated guanylate kinases (MAGUKs), Shanks, and Homers.59–61 Scaffolding proteins can be defined as molecules binding at least two other signaling proteins together. These scaffolding proteins are crucial for synaptic plasticity (e.g., learning and memory) by (1) acting as platforms where signaling molecules can assemble; (2) localizing signaling molecules at specific intracellular sites; (3) coordinating positive and negative feedback signals to modify intra- and extra-cellular signaling pathways; as well as (4) protecting these signaling pathways from inactivation, generally by preventing and/or disrupting phosphorylation.62–64 In general, scaffolding proteins act as signaling proteins for neuromodulator receptors and anchor these receptors (e.g., glutamate receptors) to the synaptic membrane.65 Given their role in receptor anchoring, dysregulation of these scaffolding proteins can lead to a number of neurological diseases.66
