|Memory > NMDAR Extinction in Spines|
Chapter 12 suggests that binding of the CABT complex to GluN2B may cause the GluN2B-containing NMDA receptors (NMDARs) to enter an extinction state which is also called "desensitized state" (Aman et al., 2014; Tong et al., 1995). What are the biological processes that cause CABT to bind and inhibit NMDAR? The answer may depend on whether NMDARs are located in dendritic spines or dendritic shaft. As shown below, the CABT complex might be transported into spines by microtubules during strong synaptic stimulation. The next chapter will show that NMDARs in the shaft could be inhibited by CABT resulting from Ca2+-induced microtubule depolymerization.
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 cargo transported by dynamic microtubules into spines could be the CABT complex, which has been shown to be transported by microtubules via the motor protein Kinesin-1 (more info). This notion is further supported by a recent report that overexpression of CRMP2 results in an increase of mushroom-shape spines (Zhang et al., 2018).
Author: Frank Lee