Dynamic Microtubules Regulate Dendritic Spine Morphology and Synaptic Plasticity

Abstract

Dendritic spines are the major sites of excitatory synaptic input, and their morphological changes have been linked to learning and memory processes. Here, we report that growing microtubule plus ends decorated by the microtubule tip-tracking protein EB3 enter spines and can modulate spine morphology. We describe p140Cap/SNIP, a regulator of Src tyrosine kinase, as an EB3 interacting partner that is predominantly localized to spines and enriched in the postsynaptic density. Inhibition of microtubule dynamics, or knockdown of either EB3 or p140Cap, modulates spine shape via regulation of the actin cytoskeleton. Fluorescence recovery after photobleaching revealed that EB3-binding is required for p140Cap accumulation within spines. In addition, we found that p140Cap interacts with Src substrate and F-actin-binding protein cortactin. We propose that EB3-labeled growing microtubule ends regulate the localization of p140Cap, control cortactin function, and modulate actin dynamics within dendritic spines, thus linking dynamic microtubules to spine changes and synaptic plasticity.

The role of the drebrin/EB3/Cdk5 pathway in dendritic spine plasticity, implications for Alzheimer’s disease

“…There is now considerable evidence that microtubule invasion of dendritic spines underlies morphological and physiological changes associated with memory formation including F-actin stabilization, spine maturation and enlargement of the PSD . Consistent with these findings, shRNA-mediated knock-down of EB3 reduces spine enlargement (Gu et al 2008;Jaworski et al 2009). An early event in dendritic spine enlargement associated with increased synaptic strength is an enlargement of the PSD and a concomitant increase in PSD-95, the major scaffolding protein of the PSD.…”

“…Dynamic microtubules in dendrite shafts can transiently enter dendritic spines by polymerizing from their plus-ends, the end at which tubulin assembly occurs preferentially (Gu et al 2008;Hu et al 2008;Jaworski et al 2009;Wagner et al, 2011;Merriam et al, 2013). The frequency of invasion is low, with approximately 1% of dendritic protrusions containing a microtubule at any one time (Hu et al 2008) and the dwell time is in the order of minutes but, importantly, dwell time and the frequency of invasion are enhanced by pharmacological interventions that mimic LTP (Gu et al 2008, Hu et al 2008Mitsuyama et al 2008;Jaworski et al 2009;Merriam et al 2011) and supressed by eliciting LTD (Kapitein et al 2011).…”

“…The frequency of invasion is low, with approximately 1% of dendritic protrusions containing a microtubule at any one time (Hu et al 2008) and the dwell time is in the order of minutes but, importantly, dwell time and the frequency of invasion are enhanced by pharmacological interventions that mimic LTP (Gu et al 2008, Hu et al 2008Mitsuyama et al 2008;Jaworski et al 2009;Merriam et al 2011) and supressed by eliciting LTD (Kapitein et al 2011). Depolymerisation of microtubules in dendrites using drugs such as nocodazole reduces spine density along the dendrite without affecting dendrite numbers (Jaworski et al, 2009). Dendritic microtubules are oriented with their plus-ends directed either towards or away from the cell body and can therefore polymerise antero-or retrogradely, and can be nucleated acentrosomally within the dendrite (Delandre et al, 2016).…”

Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis

“…The rationale for including p140Cap in the assay results from our previous demonstration that acute downregulation of SNAP-25 impairs spines morphogenesis through p140Cap, 23 a synaptic protein involved in Src-kinase regulation and microtubules organization inside the spine. 41 The well-characterized protein/protein interaction (Figure 5c). Results indicated that SNAP-25 and PSD-95 do not interact directly, whereas p140Cap specifically interacts with PSD-95 (Figure 5c).…”

Integrin signalling adaptors: not only figurants in the cancer story

“…p140CAP has been shown to co-localize with actin stress fibres and cortical actin and to associate with proteins involved in actin cytoskeleton dynamics, such as p130CAS, SRC, VINEXIN and CORTACTIN 41,42,119 . These findings along with the presence of a putative actin-binding domain in p140CAP (Figure 1), suggest that this adaptor could be directly or indirectly involved in actin filaments assembly.…”