Chapter 5 - ECM receptors in neuronal structure, synaptic plasticity, and 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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2022, Molecular Therapy Nucleic AcidsCitation Excerpt :Their overactivation is involved in diverse pathologies, including cancer and thrombosis, and thus they represent a target of choice for developing drug therapies based on pharmacological inhibitors.19 In the brain, integrins regulate synaptic connectivity and plasticity in response to chemical and mechanical cues.13,16,20–23 The two most abundant neuronal integrins are β1 and β3, which have non-overlapping functions.