Dynamic Microtubules Promote Synaptic NMDA Receptor-Dependent Spine Enlargement

Abstract

Most excitatory synaptic terminals in the brain impinge on dendritic spines. We and others have recently shown that dynamic microtubules (MTs) enter spines from the dendritic shaft. However, a direct role for MTs in long-lasting spine plasticity has yet to be demonstrated and it remains unclear whether MT-spine invasions are directly influenced by synaptic activity. Lasting changes in spine morphology and synaptic strength can be triggered by activation of synaptic NMDA receptors (NMDARs) and are associated with learning and memory processes. To determine whether MTs are involved in NMDAR-dependent spine plasticity, we imaged MT dynamics and spine morphology in live mouse hippocampal pyramidal neurons before and after acute activation of synaptic NMDARs. Synaptic NMDAR activation promoted MT-spine invasions and lasting increases in spine size, with invaded spines exhibiting significantly faster and more growth than non-invaded spines. Even individual MT invasions triggered rapid increases in spine size that persisted longer following NMDAR activation. Inhibition of either NMDARs or dynamic MTs blocked NMDAR-dependent spine growth. Together these results demonstrate for the first time that MT-spine invasions are positively regulated by signaling through synaptic NMDARs, and contribute to long-lasting structural changes in targeted spines.

Synaptic Regulation of Microtubule Dynamics in Dendritic Spines by Calcium, F-Actin, and Drebrin

“…3C,D), increases in MTspine invasions peak in the minutes following NMDAR activation and persist Ͼ30 min later ( Fig. 3C; Merriam et al, 2011). Furthermore, although MTs enter spines from the neighboring dendrite (Fig.…”

“…In a previous study, we found that MT-spine invasions are promoted by activation of synaptic NMDARs; Merriam et al, 2011). Since NMDAR channel opening results in a large flux of calcium ions into the spine, we hypothesized that elevations in intracellular calcium may influence MT entry into spines.…”

“…MT entry into spines is associated with both spine enlargement and increased spine PSD-95 content , and may be directly involved in trafficking of molecular cargos to and from the synapse (Schapitz et al, 2010;Dent et al, 2011a). While MTs enter spines spontaneously, spine invasions are also positively regulated by membrane depolarization and by stimulation of synaptic NMDA receptors (NMDARs; Merriam et al, 2011). In contrast, stimulation of both synaptic and extrasynaptic NMDARs by bath application of NMDA results in a loss of MT dynamics in dendrites and spines (Kapitein et al, 2011).…”

Microtubule nucleation and organization in dendrites

“…8 In addition, they regulate neuronal plasticity through activity-dependent remodeling, with microtubule invasion events driving spine enlargement and increases in post synaptic density protein levels. [9][10][11][12] Furthermore, microtubules support channel activity 13 ; for example, the coupling of the transient receptor potential family mechanotransduction channel NompC to an array of microtubules conveys force to gate channel activation. [14][15][16] Dendrite microtubule architecture differs between neuron types 15,[17][18][19][20] in order to support the specific functional requirements of each type.…”

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

“…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).…”