Geon Tubulin Inhibition of NMDA Receptors in Spines Memory

 

Chapter 11 proposes that binding of tubulin to GluN2B may result in NMDAR extinction. What are the biological processes that cause tubulin to bind and inhibit NMDAR? The answer may depend on whether NMDARs are located in dendritic spines or dendritic shaft. As shown below, both tubulin and CRMP2 might be transported into spines by microtubules during strong synaptic stimulation. The next chapter will show that the NMDARs in the shaft could be inhibited by free tubulin resulting from Ca2+-induced microtubule depolymerization.

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Figure 14-1. Illustration for the microtubule invasion into spines, which requires calcium, F-actin, and drebrin (Merriam et al., 2013). [Source: Dent, 2017]

The evidence that microtubules might play a role in synaptic plasticity came in 2008, when three independent groups reported that microtubules could enter spines in an activity-dependent manner (reviewed in Dent, 2017). Upon strong synaptic stimulation, microtubules were shown to polymerize all the way to postsynaptic density (PSD) (Figure 14-1) and, within 20 seconds to 30 minutes, depolymerize back to the dendritic shaft (Hu et al., 2008). The functional role of the transient entry into spines is not clear.

The major function of microtubules is to transport various cargoes such as proteins and mitochondria. Presumably, during the short visit to spines, microtubules must bring in certain cargoes that are important for synaptic plasticity. However, the particular cargoes remain elusive. CaMKII is an essential protein in spines, but its entry into spines and PSD depends on F-actin, not microtubules (see this figure). PSD-95, another crucial protein in spines, is regulated by brain-derived neurotrophic factor (BDNF). Although the BDNF-mediated increase of PSD-95 in spines requires dynamic microtubule invasion, PSD-95 was not directly transported along microtubules into dendritic spines (Hu et al., 2011).

The present model suggests that the major cargoes transported by dynamic microtubules into spines could be tubulin and CRMP2. Tubulin is the canonical binding partner of CRMP2. It has been demonstrated that the tubulin/CRMP2 complex can be transported by microtubules via the motor protein Kinesin-1 (Kimura et al., 2005).

 

Author: Frank Lee
First Published: October, 2017
Last updated: January, 2018