Learning-induced and stathmin-dependent changes in microtubule stability are critical for memory and disrupted in ageing

Uchida, Shinichi; Martel, Guillaume; Pavlowsky, Alice; Takizawa, Shuichi; Hevi, Charles; Watanabe, Yoshifumi; Kandel, Eric R.; Alarcón, Juan Marcos; Shumyatsky, Gleb P.

doi:10.1038/ncomms5389

Cited by 79 publications

(118 citation statements)

References 71 publications

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“…Supporting this idea, acute nocodazole treatment, which resulted in increased MT dynamics, could rescue defective DD remodeling in tba-1(gf) dlk-1(0) . Although MTs in mature axons are predominantly stable, it is being increasingly appreciated that dynamic MTs are important for a variety of neuronal processes, including axon regeneration [15, 33], dendritic spine growth [34] and memory formation [35]. Our studies reveal a specific role for dynamic MTs in modulating plasticity of pre-synaptic terminals, independent of axon outgrowth.…”

Section: Discussionmentioning

confidence: 73%

Dynamic Microtubules Drive Circuit Rewiring in the Absence of Neurite Remodeling

et al. 2015

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A striking neuronal connectivity change in C. elegans involves the coordinated elimination of existing synapses and formation of synapses at new locations, without altering neuronal morphology. Here, we investigate the tripartite interaction between dynamic microtubules (MTs), kinesin-1, and vesicular cargo during this synapse remodeling. We find that a reduction in the dynamic MT population in motor neuron axons, resulting from genetic interaction between loss of function in the conserved MAPKKK dlk-1 and an α-tubulin mutation, specifically blocks synapse remodeling. Using live imaging and pharmacological modulation of the MT cytoskeleton, we show that dynamic MTs are increased at the onset of remodeling and are critical for new synapse formation. DLK-1 acts during synapse remodeling, and its function involves MT catastrophe factors including kinesin-13/KLP-7 and spastin/SPAS-1. Through a forward genetic screen, we identify gain-of-function mutations in kinesin-1 that can compensate for reduced dynamic MTs to promote synaptic vesicle transport during remodeling. Our data provide in vivo evidence supporting the requirement of dynamic MTs for kinesin-1 dependent axonal transport and shed insight on the role of the MT cytoskeleton in facilitating neural circuit plasticity.

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Section: Discussionmentioning

confidence: 73%

Dynamic Microtubules Drive Circuit Rewiring in the Absence of Neurite Remodeling

et al. 2015

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“…In this review we will focus mostly on the tyrosination/tyrosination of tubulin because recent work has shown its critical role in memory formation (Uchida et al, 2014). α-tubulin undergoes the tyrosination/detyrosination cycle.…”

Section: Post-translational Modifications (Ptms) Of Tubulinmentioning

confidence: 99%

“…Indeed, recent evidence in live animals has revealed a previously unknown feature of microtubules: learning induces biphasic shifts in microtubule stability in the dentate gyrus of hippocampus (Uchida et al, 2014). The level of detyrosinated tubulin (marker of stable microtubules) was changed in a biphasic manner, first decreasing within 30–60 min following contextual fear conditioning and then increasing at the time point of 8 h following conditioning, whereas tyrosinated tubulin (marker of unstable microtubules) levels were changed in the opposite direction (Table 1).…”

Section: Microtubules In Synaptic Plasticity and Memory Formationmentioning

confidence: 99%

“…Thus, it is likely that microtubule dynamics in the dendritic spines and surrounding areas play important roles in synaptic plasticity and memory formation. Indeed, recent work in animals has begun to show that microtubule dynamics at synaptic sites are controlled by activity and learning, and that these changes are critical for long-term potentiation (LTP) and memory (Fanara et al, 2010; Uchida et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

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Deceivingly dynamic: Learning-dependent changes in stathmin and microtubules

Uchida

Shumyatsky

2015

Neurobiology of Learning and Memory

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Microtubules, one of the major cytoskeletal structures, were previously considered stable and only indirectly involved in synaptic structure and function in mature neurons. However, recent evidence demonstrates that microtubules are dynamic and have an important role in synaptic structure, synaptic plasticity, and memory. In particular, learning induces changes in microtubule turnover and stability, and pharmacological manipulation of microtubule dynamics alters synaptic plasticity and long-term memory. These learning-induced changes in microtubules are controlled by the phosphoprotein stathmin, whose only known cellular activity is to negatively regulate microtubule formation. During the first eight hours following learning, changes in the phosphorylation of stathmin go through two phases causing biphasic shifts in microtubules stability/instability. These shifts, in turn, regulate memory formation by controlling in the second phase synaptic transport of the GluA2 subunit of AMPA receptors. Improper regulation of stathmin and microtubule dynamics has been observed in aged animals and in patients with Alzheimer’s disease and depression. Thus, recent work on stathmin and microtubules has identified new molecular players in the early stages of memory encoding.

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“…In mammals, it is known that amygdala enriched stathmin is required for the expression of innate fear and the formation of memory for learned fear [67][68][69]. Interestingly, Ov-stm undergoes in the octopus to a negative regulation in response to fear conditioning.…”

Section: Criterion Judgement Notesmentioning

confidence: 99%