Chapter 5 - ECM receptors in neuronal structure, synaptic plasticity, and behavior

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Abstract

During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity. These receptors bind to and are activated by ECM ligands. In turn, ECM receptor activation modulates downstream signaling cascades that control cytoskeletal dynamics and synaptic activity to regulate neuronal structure and function and thereby impact animal behavior. The activities of cell adhesion receptors that mediate interactions between pre- and postsynaptic partners are also strongly influenced by ECM composition. This chapter highlights a number of ECM receptors, their roles in the control of synapse structure and function, and the impact of these receptors on synaptic plasticity and animal behavior.

Introduction

During early postnatal development, the nervous system is highly plastic, continuously forming, eliminating, and remodeling dendrites and dendritic spines. This plasticity allows for proper synaptic connectivity to develop in an experience-dependent fashion. At early developmental ages, the extracellular matrix (ECM) provides a dynamic and permissive environment to allow for heightened neuronal plasticity (Dansie and Ethell, 2011, Kochlamazashvili et al., 2010). As the brain matures, the ECM is remodeled and replaced by an adult form that is localized to the intercellular space between neurons and glia. Additionally, the adult ECM is found in specialized structures, including perineuronal nets (PNNs) that surround interneurons. This adult ECM provides an external physical barrier to restrict dendrite and dendritic spine plasticity (Dityatev and Schachner, 2003). In addition to acting as a scaffold, ECM proteins can bind specifically to cell surface receptors, activating signaling cascades to regulate neuronal function (Dansie and Ethell, 2011). This chapter will review the functions of important ECM receptors in the brain, including integrins, syndecans, agrin, lipoprotein receptors (LPRs), and tetraspanins.

Section snippets

Membrane-Bound Heparan Sulfate Proteoglycans

Heparan sulfate proteoglycans are composed of a protein core to which multiple linear polysaccharide heparan sulfate (HS) molecules are covalently linked (Ethell and Yamaguchi, 1999, Winzen et al., 2003). In the brain, the heparan sulfate proteoglycan (HSPG) family includes both syndecans and agrin receptors, which regulate diverse processes, discussed in detail here.

Link to Human Brain Disease

Studies of knockout mice or knockdown of ECM receptors in cultured neurons reveal that they play critical roles in the development of synaptic connectivity, long-term synapse and dendrite maintenance, synaptic plasticity, and overall learning and memory. These observations strongly suggest that dysfunction of ECM receptors plays central roles in brain diseases that are associated with defects in dendrite, dendritic spine, and synapse development, function, stability, and plasticity. These

Questions and Directions for Future Research

ECM molecules and their receptors play important roles in the formation, maintenance, and plasticity of the nervous system. As ECM receptors are cell surface receptors, they make ideal drug targets for small molecules that could either prevent or mimic ligand binding to impact intracellular signaling cascades and treat human brain diseases. Also, the downstream signaling cascades by which they function will also be key potential targets for therapeutic intervention. Some ECM receptor signaling

Acknowledgments

This work was supported by grants from the National Institute of Health (NIH) NS39475, GM100411, and CA133346, the European Research Council (ERC; #334218), the Italian Institute of Technology (IIT), and the COST Action BM1001 “Brain Extracellular Matrix in Health and disease.” We thank Aaron Levy, Yu-Chih Lin, and Mitchell Omar for their helpful comments on this chapter.

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