The microtubule cytoskeleton at the synapse

Abstract

In neurons, microtubules (MTs) provide routes for transport throughout the cell and structural support for dendrites and axons. Both stable and dynamic MTs are necessary for normal neuronal functions. Research in the last two decades has demonstrated that MTs play additional roles in synaptic structure and function in both pre- and postsynaptic elements. Here, we review current knowledge of the functions that MTs perform in excitatory and inhibitory synapses, as well as in the neuromuscular junction and other specialized synapses, and discuss the implications that this knowledge may have in neurological disease.

Keywords: AMPA; Active zone; Dendritic spines; En passant boutons; GABA(A); Kif1A; Microtubules; NMDA; Postsynaptic density; Synapses; Synaptic vesicle; Synaptotagmin IV.

Figure 1.. Schematic of MT functions in two different types of postsynaptic elements.

(A) Excitatory postsynaptic site: depolarization of the dendritic spine allows for transient entry of dynamic MTs into the spine. Entry of dynamic MTs into spines has been associated with structural plasticity of the invaded spines. Selective dendritic spine delivery of SytIV is mediated by the MT plus end motor Kif1A. Entry of dynamic MTs into the spine is regulated by the MT plus end binding protein EB3, which can bind to F-actin and F-actin regulators residing in the spine, such as drebrin and cortactin. EB3 is also a binding partner of STIM2, an ER membrane protein and a regulator of Ca²⁺ dynamics in mushroom spines. This binding may provide an additional pathway for entry of STIM2/smooth endoplasmic reticulum (sER) into the spine. (B) Inhibitory postsynaptic site: the postsynaptic element of inhibitory synapses is typically located directly on the dendrite, cell body or axon hillock. Inhibitory synapses can be glycinergic, GABAergic or mixed. Gephyrin acts as a scaffold protein, anchoring glycine and GABA receptors to the microtubule cytoskeleton. While the lateral diffusion of glycine receptors (GlyRs) in the synapse is affected by F-actin, lateral diffusion outside of the synapse is controlled by MTs, a mechanism that may be important for the dynamic regulation of the neuronal membrane “apparent viscosity” to control the “influx” and “efflux” of receptors at the synapse during synaptic plasticity.

Figure 2.. Schematic of MT functions in different types of presynaptic elements.

(A) Excitatory presynaptic bouton: by EM, MTs can be found associated with mitochondria and SVs close to the active zone. Functional studies have ascribed a role for γ-tubulin and augmin de novo nucleated MTs at presynaptic en passant boutons in the regulation of neuronal transmission by limiting the rate of bidirectional interbouton SV transport and Kif1A-mediated SV delivery and unloading to sites of release. (B) In the goldfish retinal bipolar neurons, MTs loop into the presynaptic bouton to organize and anchor mitochondria in the presynaptic area. (C) In the mammalian auditory CNS, the giant calyx of Held synapse surrounds the soma of the MNTB (Medial Nucleus of the Trapezoid Body) principal cell. In calyceal terminals, presynaptic MTs extend throughout the presynaptic area and organize SVs and MAC superstructures. MTs also play essential roles in inter-synaptic movements of SVs that are rate limiting for high-frequency neurotransmission. (D) In the presynaptic bouton of the NMJ, MTs form a loop in the presynaptic area, which is stabilized by Futsch/MAP1B. This loop is important in the budding process of newly forming boutons. Synaptic vesicles have also been observed on MTs that approach the active zone.