Memory  >   Memory Consolidation: CRMP2 Directs Neurite Growth

The role of CRMP2 in axons has been extensively investigated. It is now well-established that CRMP2 can bind tubulin and promote axonal branching and outgrowth (Fukata et al., 2002; Yoshimura et al., 2005; Xia et al., 2013; Balastik et al., 2015; Niwa et al., 2017). Several lines of evidence suggest that CRMP2 could also play an important role in dendrites:

Furthermore, the antibody against CRMP2 causes amnesia (Mileusnic and Rose, 2011), which underscores its importance in memory. The previous chapters propose that the CABT complex formed by a CRMP2 monomer and a tubulin heterodimer could play a central role in memory extinction. This chapter focuses on its role in memory consolidation.

The Role of Myosin II in Consolidation

Myosin II is one of the motor proteins employed by the actin cytoskeleton. Its expression and motor activity within the hippocampal CA1 are essential for long-term memory consolidation (Rex et al., 2010). Myosin II also plays an important role in the lateral amygdala for fear memory consolidation, as infusions of its inhibitor into this region disrupted the formation of long term memory, while short-term memory was unaffected (Gavin et al., 2011). In addition, Myosin II is implicated in methamphetamine-associated memory (Young et al., 2016; Young et al., 2017). Myosin II directly alters cytoskeletal dynamics through ATPase-driven contraction of F-actin (Rex et al., 2010), unlike other motor proteins (e.g., Myosin V and VI) which carry cargos along the F-actin (Figure 26-2). Myosin II has been shown to mediate the translocation of stable F-actin (bound by drebrin A) from spines to the dendritic shaft (Mizui et al., 2014).

Colocalization of the CABT complex with F-actin has been observed in neurites (Tan et al., 2015; Yang et al., 2015), suggesting that CABT could bind F-actin in the spine head, resulting in mushroom-shape spines (Zhang et al., 2018). More specifically, CABT could bind either the dynamic F-actin in the upper part of the spine head or the stable F-actin in the lower part of the spine head. The Ca2+ influx through GluN2B-containing NMDARs may activate AKAP-anchored calcineurin to enhance cofilin activity, resulting in the depolymerization of the nearby dynamic F-actin. This could cause CABT to dissociate from dynamic F-actin and block GluN2B-NMDARs, consequently leading to NMDAR extinction (see Chapter 20). Other sources of Ca2+ may activate Myosin II (Somlyo and Somlyo, 2003). The finding that Myosin II mediates the translocation of stable F-actin from spines to the dendritic shaft indicates that the CABT complexes that bind the stable F-actin can also be transported to the dendritic shaft. CABT complexes cannot induce neurite growth while confined in spines. They should move to the dendritic shaft to exert this function. Since neurite growth is crucial for synaptogenesis during memory consolidation, Myosin II may promote memory consolidation by transporting CABT complexes from dendritic spines to the shaft.

The Role of CRMP2 in Consolidation

Once in the dendritic shaft, CABT complexes may orchestrate dendritic branching and elongation. Recalling that a dendritic branch may serve as a memory unit (Chapter 9). The elongation of a dendritic branch allows the memory unit to contain more synapses, thereby strengthening the memory unit. The dendritic branching increases the number of branches (memory units), thus expanding memory capacity.

To generate synapses, dendritic growth in the postsynaptic neuron should be accompanied by corresponding presynaptic axonal growth, which is also directed by CRMP2. Recently, it was found that the translation of CRMP2 from its mRNA is regulated by mTORC1 (Na et al., 2017). Several pathways may lead to the activation of mTORC1. One of them is the BDNF-TrkB signaling (see this article). The expression of brain-derived neurotrophic factor (BDNF), in turn, is regulated by the PKA/CREB/BDNF pathway (Lonze and Ginty, 2002). As expected, protein kinase A (PKA) is involved in memory consolidation (Schafe et al., 1999; Cho et al., 2018). Moreover, drug addiction is caused by excessive memory consolidation involving mTORC1. The mTORC1-dependent translation of CRMP2 has been demonstrated to drive the excessive alcohol-drinking behavior (Chapter 30).


Figure 27-1. A model for the involvement of CRMP2 in memory consolidation. Left: Ca2+ may activate Myosin II, resulting in translocation of CRMP2 (together with tubulin) from spines to the dendritic shaft. Right: Enhanced PKA activity may lead to activation of mTORC1, resulting in higher level of CRMP2 for neurite growth.


Author: Frank Lee
First published: July, 2018