BDNF-Induced Increase of PSD-95 in Dendritic Spines Requires Dynamic Microtubule Invasions

Abstract

Microtubules (MTs) are capable of entering dendritic spines in mature hippocampal neurons through dynamic polymerization. Although these MT invasions are directly associated with neuronal activity, their function remains unknown. Here we demonstrate in mouse hippocampal neurons that MT entries into spines regulate the increase in post-synaptic density protein-95 (PSD-95) after brain-derived neurotrophic factor (BDNF) treatment. Using multi-wavelength total internal reflectance fluorescence microscopy (TIRFM) we show that BDNF prolonged the average MT dwell time in spines and this effect was dependent on TrkB receptor activation. Further examination revealed that peaks of MT polymerization into spines corresponded to rapid PSD-95 increases in the spine head. Over time, spines targeted by MTs after BDNF application, but not before, showed a robust increase in PSD-95. Conversely, spines completely devoid of MT invasions showed no significant change in the level of PSD-95. Pharmacological inhibition of MT dynamics abolished the BDNF-induced increase in PSD-95. Together these results support the hypothesis that the well known increase in PSD-95 within spines after BDNF treatment is dependent on MT invasions of dendritic spines. Thus, our study provides a direct link between dynamic MTs and the post-synaptic structure, and provides a functional role for MT invasion of dendritic spines.

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.…”

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

“…To understand the mechanism by which tau knockdown impairs learning and memory, we examined changes in various proteins known to be involved in memory formation and synaptic plasticity (Hu et al., 2011; Kowiański et al., 2017). We first examined the levels of hippocampal brain‐derived neurotrophic factor (BDNF) by Western blot.…”

“…Tau is also found at postsynaptic sites where it directly interacts with the PSD95/NMDA receptor complex (El‐Husseini et al., 2000; Hu et al., 2011). In primary hippocampal neurons, NMDA receptor activation leads to tau phosphorylation, which in turn interacts with PSD95 to promote synaptic plasticity (Hu et al., 2011).…”

“…In primary hippocampal neurons, NMDA receptor activation leads to tau phosphorylation, which in turn interacts with PSD95 to promote synaptic plasticity (Hu et al., 2011). Notably, BDNF upregulation increases the size of PSD95 puncta in spines and the overall amount of PSD95 and synaptophysin (Hu et al., 2011; Yoshii & Constantine‐Paton, 2007). Thus, it is tempting to speculate that the decrease in tau levels reduces BDNF levels, which in turn reduces the amount of PSD95.…”

“…As discussed above, there is clear evidence for a physiological role of tau in synaptic plasticity (Frandemiche et al., 2014; Hu et al., 2011). Conversely, hyperphosphorylated tau accumulates in synaptic spines and alters synaptic function in a mouse model of AD (Hoover et al., 2010).…”