Regulation Of Dendritic Spine Morphology And Synaptic Function By Scaffolding Proteins

Stefano Romorini, Giovanni Piccoli, and Carlo Sala'

1. SUMMARY

Glutamate receptors on central nervous system (CNS) synapses are directly or indirectly associated with various scaffold proteins, most of which are localized at the postsynaptic density (PSD). Although the function of a number of these proteins is still unknown, it is now generally accepted that some regulate dendritic spine morphology and synapse function. Scaffold proteins bind and recruit proteins that regulate actin cytoskeleton remodeling and signaling transduction, thus linking neurotransmitter receptor activation to intracellular cytoskeletal and signaling modifications. Interestingly, mutations of some of these scaffold proteins have been implicated in the manifestation of severe forms of mental retardation and autism, which suggests that they are fundamental elements for synapse and dendritic spine structure and function. The aim of this review is to summarize recent findings concerning the scaffold protein functions involved in regulating the morphology of dendritic spines and, consequently, the function of excitatory synapses.

2. INTRODUCTION

Neurons communicate with each other using specialized cell junctions known as synapses. An individual neuron receives two major types of synaptic input, excitatory and inhibitory, which enormously differ in their molecular composition, morphology and function. Excitatory synapses are localized mostly at dendritic spines and are asymmetric synapses at the electron microscopic images due to the presence of a distinct structure known as the PSD. In contrast, inhibitory synapses

*CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, Department of Pharmacology, University of Milan, Via Vanvitelli 32, Milan 20129, Italy; [email protected]

are essentially formed on the dendritic shaft and are mostly void of a structurally defined PSD (symmetric synapses). In this chapter we focus on discussing the recent discoveries on the machinery involved in the differentiation of excitatory synapses. In particular we focus on scaffold proteins involved in regulating excitatory synapses function and morphology.

Over the last 10 years, a number of scaffold proteins have been identified and cloned as major components of the PSD in excitatory synapses. Some of these proteins were identified biochemically and genetically because of their specific synapse localization. The first scaffold proteins to be identified were members of the PSD-95 family, which are currently considered to be among the most abundant proteins in the PSD. PSD-95 is by far the most widely studied and probably one of the most important PSD scaffold proteins. The PSD-95 family of proteins associates with a number of receptors and transmembrane proteins, and is also coupled to various scaffold and signaling proteins. For example coupling of PSD-95 to GKAP/SAPAP proteins links it to Shank, which in turn binds to another important PSD-resident protein family called Homer.

The complex formed by these four proteins is apparently a major component of the PSD (see Chapter 17 for a description of how the complex is assembled at postsynaptic sites during synapse formation) and thus is thought to play a critical role in the development and stability of excitatory contacts.

Although their association with the PSD is regulated by synaptic activity, these scaffold proteins can be considered among key resident molecules in the PSD, but there are also various other scaffold proteins and actin-binding proteins that probably shuttle in and out of the PSD and synapse, thus regulating actin polymerization upon glutamate receptor stimulation. The PSD is therefore a highly complex structure in which resident and shuttling proteins are involved in organizing signaling at synapses. A number of scaffold proteins are formed by combining modules of protein domains whose function is protein-protein interactions. One of the most abundant interaction domains used by synaptic proteins is the PSD-95/Dlg/ZO-1 homology (PDZ) domain. PSDs are localized at the tip of small dendritic protrusions known as dendritic spines. Most of the dendritic spine cytoskeleton consists of F-actin, which is why various actin-binding scaffold proteins are concentrated in the spines. The development of these spines will be mainly discussed in Chapter 10, whereas we discuss how a number of the PSD scaffold proteins regulate dendritic spine morphology. The importance of studying spine morphogenesis is related to the fact that various genetic diseases have been identified in which defects in dendritic spine morphology are associated with cognitive disorders such as mental retardation and autism. Future challenges will be to analyze the function of these scaffold proteins in detail in order to discover which of the molecular mechanisms regulating spine formation and synapse function are deregulated in such a way as to cause mental disabilities.

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