Cytoskeletal regulation guides neuronal trafficking to effectively supply the synapse

Abstract

The development and proper function of the brain requires the formation of highly complex neuronal circuitry. These circuits are shaped from synaptic connections between neurons and must be maintained over a lifetime. The formation and continued maintenance of synapses requires accurate trafficking of presynaptic and postsynaptic components along the axon and dendrite, respectively, necessitating deliberate and specialized delivery strategies to replenish essential synaptic components. Maintenance of synaptic transmission also requires readily accessible energy stores, produced in part by localized mitochondria, that are tightly regulated with activity level. In this review, we focus on recent developments in our understanding of the cytoskeletal environment of axons and dendrites, examining how local regulation of cytoskeletal dynamics and organelle trafficking promotes synapse-specific delivery and plasticity. These new insights shed light on the complex and coordinated role that cytoskeletal elements play in establishing and maintaining neuronal circuitry.

Figure 1:

Multiple levels of regulation control long-distance microtubule trafficking in dendrites and axons. Neurons contain distinct subcellular compartments: axon (in black) hosts presynapses that pass on propagating signals to neighboring dendrites (in blue) that host postsynapses. A) Microtubules are formed from the polymerization of α/β-tubulin heterodimers. GTP-tubulin is added to the growing plus end, and after lattice incorporation the GTP-tubulin is hydrolyzed to GDP-tubulin. B, C) Microtubules are distinctly organized depending on which neuronal process they inhabit. Axonal microtubules are uniformly organized with GTP-rich dynamic plus-ends facing the distal axon. In contrast, microtubules are organized with mixed polarity in mammalian dendrites. D, E) Microtubule motor traffic is distinct in axons and dendrites. In axons, kinesin-1, −2, and −3 family motors move anterogradely toward the microtubule plus-end, while dynein/dynactin motors are responsible for retrograde trafficking toward the microtubule minus-end. In dendrites, kinesin-2, −3, and −4 family motors and dynein/dynactin motors can move cargo in either the anterograde or retrograde direction, depending on the orientation of their individual microtubule tracks. F, G) Microtubule post-translational modifications (PTMs) are differentially distributed across neuronal compartments. Axons contain acetylated, polyglutamylated, polyaminated, detyrosinated, and tyrosinated microtubules, with detyrosination enriched in the axon shaft and tyrosination enriched in the distal axon. Dendrites contain polyglutamylated, polyaminated, acetylated, and tyrosinated microtubules, with acetylation enriched on plus-end-out microtubule arrays and tyrosination enriched on plus-end-in microtubule arrays. H, I) Microtubule-associated proteins (MAPs) preferentially localize to microtubules in distinct subcellular compartments and regulate microtubule behavior and spatially distinguish motor accessibility. MAP7, MAP9, and Tau can decorate both axonal and dendritic microtubules, while DCX, DCLK1, MAP2, and SEPT9 are specifically enriched on dendritic microtubules.

Figure 2:

Local regulation of cytoskeletal and motor dynamics dictates precise delivery of presynaptic components. A) Synaptic vesicle precursors are trafficked along axonal microtubules by KIF1A, which preferentially detaches from GTP-tubulin-rich microtubule ends at en passant presynapses. B) Synaptic vesicle exchange is facilitated by actin elongation, myosin-V-driven movement along actin filaments, and activity-dependent transport on augmin/γ-tubulin-nucleated microtubules. C) Dense core vesicles (DCVs) can be axonally trafficked by KIF1C, once autoinhibition has been relieved by Hook3 or PTPN21, or by KIF1A bound to Synaptotagmin-4 (Syt4). At active presynapses, phosphorylated JNK phosphorylates Syt4, which destabilizes KIF1A-Syt4 binding to promote capture of released DCVs by actin. DCVs also undergo long-distance axonal circulation via kinesin (anterograde) and dynein (retrograde).

Figure 3:

Cytoskeletal regulation of postsynaptic components. A) For dendritic trafficking of DCVs, calcium stimulates DCV loading onto KIF1A motors by promoting KIF1A-calmodulin (CaM) binding. At dendritic spines, postsynaptic density proteins TANC2 and liprin-α directly interact with KIF1A to capture DCVs. B) NMDA receptors are transported along dendritic microtubules by KIF17, which interacts with the Mint1-containing scaffolding complex to bind NMDA receptor subunit NR2B. Upon arrival at postsynaptic regions, CaMKII binds to the tail of KIF17 to trigger the release of cargo. Additionally, Neurobeachin (NBEA)-containing tubular structures extending from Rab4-positive recycling endosomes transiently enter dendritic spines to promote recycling of NMDA receptors. KIF21B and dynein help regulate receptor surface expression. C) NBEA, which localizes to the ERGIC and Golgi complex, also regulates targeting of AMPA and GABA neurotransmitter receptors to synapses. The axonally enriched kinesin-1, KIF5, is directed to dendrites by association with adaptor proteins GRIP1 and/or HAP1 to traffic AMPA or GABA receptors, respectively^,,.