The synaptic life of microtubules

Abstract

In neurons, control of microtubule dynamics is required for multiple homeostatic and regulated activities. Over the past few decades, a great deal has been learned about the role of the microtubule cytoskeleton in axonal and dendritic transport, with a broad impact on neuronal health and disease. However, significantly less attention has been paid to the importance of microtubule dynamics in directly regulating synaptic function. Here, we review emerging literature demonstrating that microtubules enter synapses and control central aspects of synaptic activity, including neurotransmitter release and synaptic plasticity. The pleiotropic effects caused by a dysfunctional synaptic microtubule cytoskeleton may thus represent a key point of vulnerability for neurons and a primary driver of neurological disease.

Figure 1.. Microtubules are dynamic polymers that can be modified post-translationally.

(A) Neurons contain acentrosomal microtubules composed of the regulated addition of α- and β-tubulin heterodimers arranged in a head to tail fashion, giving rise to a polarized polymer with a plus (β-tubulin) and a minus end (α-tubulin). Microtubule plus ends are uniformly oriented toward the distal end of axons, while microtubules are arranged with mixed polarity in dendrites. Microtubules undergo dynamic instability, the property of switching between growing (polymerizing) and shrinking (depolymerizing) states. Dynamic instability is defined by the combination of four parameters: the rates of growth and shrinkage and the frequency of the transitions between these two states, known as catastrophe (polymerization to depolymerization) and rescue (depolymerization to polymerization). (B) Upon stabilization, dynamic microtubules are substrates of numerous post-translational modifications to their α– and β-tubulin subunits, preferentially on C-terminal residues exposed to the surface of the microtubule lattice. The combinatorial nature of these modifications gives rise to a “tubulin code”, an incompletely understood collection of molecular rules regulating the affinity of microtubule binding proteins and microtubule turn-over. The location and variety of tubulin post-translational modifications (de-tyrosination, Δ2/Δ3, acetylation, polyamination, phosphorylation, polyglutamylation, polyglycylation) on α-tubulin and β-tubulin are shown.

Figure 2.. Microtubule functions in neurotransmitter release.

(A) In terminals from highly active and graded synapses such as those at the Calyx of Held and retinal bipolar neurons, presynaptic microtubules are rate limiting for high-frequency neurotransmission, serving to replenish the readily releasable pool of synaptic vesicles from the reserve pool. Presynaptic microtubules also facilitate mitochondria organization and anchoring to the membrane by forming stable peripheral bundles or maintaining MAC superstructures. (B) The Drosophila neuromuscular junction contains bundled loops of microtubules held in proximity of the AZ by microtubule-associated protein futsch/MAP1B, as well as pioneer microtubules, a subset of dynamic microtubules regulated by formin activity. These microtubules may provide the tracks for kinesin mediated delivery of SVs and dynein/BicD mediated recycling of clathrin-coated endosomes (CCE) into and out of the synaptic terminal. (C) Mammalian glutamatergic en passant boutons are hotspots for γ-tubulin- and augmin-dependent de novo nucleation of dynamic microtubules, labelled by the ⁺TIP EB3. Here, γ-tubulin regulates nucleation density and augmin coordinates the uniform, plus-end directed growth towards the distal axon. Nucleation of dynamic microtubules at boutons is stimulated by neuronal activity and regulates neurotransmission by providing the tracks for interbouton delivery of rate-limiting synaptic vesicles to sites of release.

Figure 3.. Microtubule functions in synaptic plasticity.

Dynamic dendritic microtubules can invade dendritic spines, a process promoted by NMDAR activation, Ca²⁺ influx and actin polymerization, and mediated by the neuron-specific F-actin binding proteins drebrin and cortactin. Invasion of dynamic microtubules into spines regulates spine structural plasticity, by mediating delivery of cargoes such as synaptotagmin-4 and AMPARs, as well as the synaptic localization and delivery of the Ca²⁺ sensor and ER resident protein STIM2.