The postsynaptic density

Abstract

What is the postsynaptic density (PSD)? Seen by electron microscopy (EM) as an electron-dense thickening of the postsynaptic membrane of excitatory synapses, the PSD contains a high concentration of structural and signaling proteins connected physically and functionally to postsynaptic glutamate receptors and transsynaptic adhesion molecules. This marked thickening of the postsynaptic membrane is a hallmark of excitatory synapses (hence termed asymmetric), contrasting with the symmetric inhibitory synapses that lack a prominent PSD. PSDs can be biochemically purified as insoluble multi-protein complexes by repeated detergent extraction of brain synaptosomes.What is the size of the PSD? The PSD can be disk-like or highly irregular in shape. Large PSDs often have one or more perforations. Disk-like PSDs have an average diameter of 360 nm (range 200–800 nm) and a thickness of 40 nm (30–50 nm). The molecular mass of an average PSD has been estimated at ∼1 gigadalton, although this might be an overestimate because PSDs recruit a large amount of proteins (like calcium–calmodulin-dependent protein kinase II, CaMKII) during ischemia and biochemical purification.Where is the PSD located? The PSD is usually found at the tip of dendritic spines. Spines are tiny, ∼0.5–2 μm long membrane protrusions on dendrites that receive the majority of excitatory synaptic inputs. The PSD is directly apposed to the presynaptic active zone — the site of release of the neurotransmitter glutamate (Figure 1Figure 1A). The space underneath the PSD is occupied by actin filaments, the major cytoskeletal component of dendritic spines. Neighboring the PSD are endocytic zones, which are ‘hot spots’ for endocytosis of glutamate receptors (Figure 1Figure 1A).Figure 1Schematic diagrams of a dendritic spine and a simplified molecular organization of the PSD.(A) Dendritic spine. The PSD is apposed to the presynaptic active zone, attached to F-actin in the spine, and neighbored by the endocytic zone. Smooth ER, smooth endoplasmic reticulum. (B) Core scaffold proteins of the PSD — PSD-95, GKAP, Shank, and Homer — interact with each other and other proteins (as indicated by overlap of protein shapes) and are thought to form a lattice for the assembly of postsynaptic membrane proteins and signaling molecules. AMPAR, AMPA glutamate receptor; CaMKII, calcium/calmodulin-dependent protein kinase II; mGluR, metabotropic glutamate receptor; NMDAR, NMDA glutamate receptor; SynGAP, synaptic Ras-GTPase-activating protein; TARP, transmembrane AMPA receptor regulatory protein.View Large Image | View Hi-Res Image | Download PowerPoint SlideWhat is the PSD made of? Proteomic studies have identified several hundred proteins that constitute the PSD, including glutamate receptors, ion channels, cell adhesion molecules, and signaling enzymes, as well as membrane trafficking, cytoskeletal and scaffolding proteins. The abundance of key PSD proteins has been measured, with CaMKIIα, CaMKIIβ, the Ras GTPase-activating protein SynGAP and the scaffold protein PSD-95 being most abundant. The molecular composition of the PSD varies between different neuronal cell types and different brain regions. The PSD appears to be assembled around several key scaffold proteins, including PSD-95, which has several protein–protein interaction domains (including three PDZ domains) through which it binds to a variety of membrane, signaling, and scaffolding proteins. On the cytoplasmic side of the PSD, Shank and Homer scaffold proteins interact to form a mesh-like structure. Recent EM studies are beginning to reveal the three-dimensional organization of the PSD and its constituent protein complexes.What is the function of the PSD? The PSD has structural and signaling roles. It localizes and stabilizes glutamate receptors and adhesion molecules in the postsynaptic membrane, thereby aiding synaptic adhesion and the alignment of neurotransmitter receptors to the presynaptic release sites (Figure 1Figure 1B). In addition, the PSD assembles a variety of signaling molecules close to glutamate receptors, so activation (particularly of NMDA receptors) is efficiently coupled to postsynaptic signaling pathways (Figure 1Figure 1B).How dynamic is the PSD? The PSD is highly dynamic in structure and composition. Proteins move into and out of the PSD, regulated by synaptic activity. For instance, CaMKIIα and AMPA receptors can be rapidly recruited to the PSD following synaptic stimulation. Several proteins of the PSD are turned over in response to activity via proteasomal degradation. These changes are believed to contribute to plasticity of synaptic strength and structure, such as long-term potentiation and synaptic homeostasis.Is there any connection between PSD proteins and disease? Mutations of several PSD proteins have been linked to human central nervous system disease. For instance, mutations in the PSD scaffold protein Shank3 and in the postsynaptic adhesion molecules neuroligin-3 and -4 cause autism spectrum disorder. Mutations of the PSD scaffold SAPAP3/GKAP3 may be related to obsessive compulsive disorder. Deletion of the δ-catenin gene, which encodes a cadherin-associated protein enriched in the PSD, leads to severe mental retardation.What remains to be explored? Importantly, the biochemical and physiological functions of many PSD proteins remain unknown. The detailed three-dimensional structure of the PSD is still unclear, and its dynamic regulation is poorly understood. Much remains to be discovered about how PSD proteins relate to synaptic plasticity, brain function and central nervous system disease.