Abstract
The regulation of synaptic strength forms the basis of learning and memory, and is a key factor in understanding neuropathological processes that lead to cognitive decline and dementia. While the mechanical aspects of neuronal development, particularly during axon growth and guidance, have been extensively studied, relatively little is known about the mechanical aspects of synapse formation and plasticity. It is established that a filamentous actin network with complex spatiotemporal behavior controls the dendritic spine shape and size, which is thought to be crucial for activity-dependent synapse plasticity. Accordingly, a number of actin binding proteins have been identified as regulators of synapse plasticity. On the other hand, a number of cell adhesion molecules (CAMs) are found in synapses, some of which form transsynaptic bonds to align the presynaptic active zone (PAZ) with the postsynaptic density (PSD). Considering that these CAMs are key components of cellular mechanotransduction, two critical questions emerge: (i) are synapses mechanically regulated? and (ii) does disrupting the transsynaptic force balance lead to (or exacerbate) synaptic failure? In this mini review article, I will highlight the mechanical aspects of synaptic structures—focusing mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation of synapses and its relevance to neurodegenerative diseases.
Highlights
Chemical synapses of the central nervous system (CNS) mediate the directional information flow between neurons and form the basis of learning and memory
A precisely-defined synaptic cleft separates the opposing pre- and postsynaptic terminals that are held in place via transsynaptic cell adhesion molecules (CAMs)
Recent studies established that synapse formation and plasticity require unique mechanisms involving the cytoskeleton, molecular motors, CAMs and the extracellular matrix (ECM; Figure 1). Considering that these components are either force-generating or force-bearing, two critical questions emerge: (i) are synapses mechan(ochem)ically regulated? and (ii) does disrupting the transsynaptic force balance lead to synaptic failure? In this mini review article, I will highlight the mechanical aspects of synaptic structures—focusing mainly on cytoskeletal dynamics and CAMs—and discuss potential mechanoregulation of synapses and its relevance to neurodegenerative diseases
Summary
Chemical synapses of the central nervous system (CNS) mediate the directional information flow between neurons and form the basis of learning and memory. Cortactin directly interacts with N-methyl-D-aspartate receptors (NMDARs) and Shank scaffold in the PSD, and regulates the branch-inducing Arp2/3 complex (Hering and Sheng, 2003), which is required for spine maturation (Spence et al, 2016). The microtubule plus end-binding protein EB3 directly interacts with the postsynaptic scaffold protein PSD-95, an event that decreases EB3-microtubule interaction (Sweet et al, 2011), suggesting a functional role for dendritic microtubules in synaptic plasticity.
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