ANRV313-BI76-33 ARI 1 May 2007 19:29 The Postsynaptic Architecture of Excitatory Synapses: A More Quantitative View Morgan Sheng1 and Casper C. Hoogenraad2 1The Picower Institute for Learning and Memory, Howard Hughes Medical Institute, Departments of Brain and Cognitive Sciences, and Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; email: [email protected] 2Department of Neuroscience, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands; email: [email protected] Annu. Rev. Biochem. 2007. 76:823–47 Key Words First published online as a Review in Advance on dendritic spine, glutamate receptor, mass spectrometry, December 19, 2006 postsynaptic density, PSD-95 The Annual Review of Biochemistry is online at biochem.annualreviews.org Abstract by SCELC Trial on 03/25/13. For personal use only. This article’s doi: Excitatory (glutamatergic) synapses in the mammalian brain are usu- 10.1146/annurev.biochem.76.060805.160029 ally situated on dendritic spines, a postsynaptic microcompartment Copyright c 2007 by Annual Reviews. that also harbors organelles involved in protein synthesis, membrane All rights reserved trafficking, and calcium metabolism. The postsynaptic membrane Annu. Rev. Biochem. 2007.76:823-847. Downloaded from www.annualreviews.org 0066-4154/07/0707-0823$20.00 contains a high concentration of glutamate receptors, associated sig- naling proteins, and cytoskeletal elements, all assembled by a variety of scaffold proteins into an organized structure called the postsynap- tic density (PSD). A complex machine made of hundreds of distinct proteins, the PSD dynamically changes its structure and composi- tion during development and in response to synaptic activity. The molecular size of the PSD and the stoichiometry of many major con- stituents have been recently measured. The structures of some intact PSD proteins, as well as the spatial arrangement of several proteins within the PSD, have been determined at low resolution by electron microscopy. On the basis of such studies, a more quantitative and geometrically realistic view of PSD architecture is emerging. 823 ANRV313-BI76-33 ARI 1 May 2007 19:29 cal depolarization to the postsynaptic neuron Contents (excitatory synaptic transmission). The strength of synaptic transmission can INTRODUCTION................. 824 be modified (synaptic plasticity) by various MICROANATOMY OF THE factors, including specific patterns of synaptic EXCITATORY SYNAPSE ....... 825 activity (1). By altering synaptic strength in Synaptic Cleft .................... 825 an activity-dependent manner, synaptic plas- The Dendritic Spine.............. 827 ticity allows synapses and neural networks to Organelles Within Dendritic store information in response to prior experi- Spines ........................ 828 ence, such as occurs during development and THE POSTSYNAPTIC DENSITY . 829 in learning and memory. In parallel with ad- Biochemical Composition of the justing the strength of synaptic transmission, PSD.......................... 829 neurons can change the morphology of synap- Quantitative View of PSD Protein tic connections and even their physical pat- Composition .................. 831 tern of connectivity (2). Thus information can Three-Dimensional Organization be stored long-term in the brain not only by ofthePSD.................... 835 modulation of synaptic strength but also by Three-Dimensional Structures of the formation of new synapses or the elimina- Individual Postsynaptic tion of existing synapses (2, 3). Molecules ..................... 837 Synaptic transmission and plasticity are Heterogeneity of PSD crucial for all aspects of nervous system func- Composition between Different tion and critical for proper development of Brain Regions and Cell Types. 838 the central nervous system. Normal synap- Turnover of Proteins in the PSD . 839 tic transmission depends on the proper local- Developmental Changes in the ization and arrangement of specific proteins PSD.......................... 839 on both sides of the synapse. Synaptic plas- EXTRASYNAPTIC MEMBRANE . 840 ticity is mediated by changes in the molecu- CONCLUDING REMARKS ....... 841 lar composition of synapses and in chemical modification of synaptic proteins. Pathologi- cal synapse development and/or function al- most certainly contribute to many neuropsy- by SCELC Trial on 03/25/13. For personal use only. chiatric disorders (e.g., schizophrenia, autism, INTRODUCTION mental retardation), common neurodegener- The billions of neurons in the mammalian ative diseases (e.g., Alzheimer’s disease), and Dendrite: the branched projections brain communicate with each other via spe- stroke (4, 5). Therefore, it is of fundamental Annu. Rev. Biochem. 2007.76:823-847. Downloaded from www.annualreviews.org of a neuron that cialized junctions called synapses. The vast and clinical importance to understand the bio- receive synaptic majority of these synapses occur at contacts chemical and cell biological basis of synaptic inputs conveyed by between presynaptic axons and postsynaptic function and plasticity. axons from other dendrites, and they use glutamate as the exci- We review the molecular and cellular ar- neurons tatory neurotransmitter. Glutamate released chitecture of the postsynaptic specialization of AMPA receptor from the presynaptic terminal acts upon post- glutamatergic (glutamate-releasing) synapses, (AMPAR): glutamate receptor synaptic glutamate receptor channels [primar- which make up the vast majority of cen- channel that ily AMPA (α-amino-3-hydroxy-5-methyl-4- tral synapses in mammalian brain. Not cov- mediates most of the isoxazolepropionic acid) receptors (AMPARs) ered are other types of excitatory synapses fast synaptic and NMDA (N-methyl-D-aspartic acid) re- (e.g., those using acetylcholine) and inhibitory transmission in ceptors (NMDARs)], which open to allow in- synapses, which differ in their molecular or- central excitatory + synapses flux of Na ions (and in the case of NMDARs, ganization (6, 7). The presynaptic special- also Ca2+ ions), thereby propagating electri- ization has been recently reviewed (8). The 824 Sheng · Hoogenraad ANRV313-BI76-33 ARI 1 May 2007 19:29 postsynaptic compartment is where most of naptic and extrasynaptic regions. The latter the molecular diversity of synapses lies and two terms are often used interchangeably, al- where the initial signal transduction events though it should be borne in mind that the NMDA receptor take place that lead to long-term synaptic perisynaptic membrane within 100 nm of the (NMDAR): plasticity. On the basis of recent progress in PSD probably differs in molecular content calcium-permeable this area, we aim to give a more quantita- and function from the extrasynaptic mem- glutamate receptor tive description of the postsynaptic special- brane at greater distances from the PSD. channel that ization, focusing on the postsynaptic density Extrasynaptic regions have specialized postsy- contributes to fast synaptic transmission (PSD) and emphasizing three-dimensional naptic functions and are enriched for a distinc- and that regulates (3D) structure, molecular stoichiometry, tive set of proteins, such as metabotropic glu- synaptic plasticity and spatial arrangement of postsynaptic tamate receptors (mGluRs) (14) and proteins Synaptic plasticity: components. involved in endocytosis (15) (Figure 1d ). On the ability of the most principal neurons in the mammalian synapse to alter its brain (e.g., pyramidal neurons of cortex and strength and MICROANATOMY OF THE hippocampus, Purkinje cells of cerebellum, structure EXCITATORY SYNAPSE medium spiny neurons of striatum), the post- Excitatory synapse: Ultrastructural features enable unambiguous synaptic specialization is housed on tiny actin- contact site where synaptic transmission identification of the pre- and postsynaptic rich protrusions called dendritic spines. In occurs by secretion sides of the synapse by electron microscopy contrast, inhibitory synapses are made on the of neurotransmitter (EM). Defining the presynaptic specialization shaft of the dendrite (Figure 1c). In inhibitory (glutamate) from is a cluster of synaptic vesicles (∼40 nm di- local circuit interneurons, which usually lack presynaptic neuron ameter), some of which are closely associated spines, the excitatory synapses are also made to postsynaptic neuron (“docked”) with a thickening of the presynap- on the dendritic shaft. The PSD (and hence tic plasma membrane (the active zone), where the synaptic contact) is typically located on the Postsynaptic density (PSD): an vesicle exocytosis occurs (8) (Figure 1a,b). dilated tip (“head”) of the spine. The dimen- electron-dense Directly apposed to the active zone (and per- sions of the spine head are highly correlated structure at the fectly matched with it in size and shape) is with the size of the PSD and associated active postsynaptic the PSD, an electron-dense thickening of the zone, as well as synaptic strength (16). membrane postsynaptic membrane, where glutamate re- containing many glutamate receptors, ceptor channels and their associated signaling Synaptic Cleft scaffold proteins, and proteins are highly concentrated (Figure 1a- signal transduction by SCELC Trial on 03/25/13. For personal use only. c). The presence of a prominent PSD is char- Separating the PSD and the active zone is molecules acteristic of glutamatergic synapses (hence the synaptic cleft, which measures ∼20 nm EM: electron they are termed asymmetric); in contrast, in- wide in conventional EM and ∼24 nm wide microscopy hibitory