|Memory > Memory Consolidation: Formation of Enduring Memory|
Memory consolidation refers to the process that converts short-term memory into long-lasting memory (> 1 month). While long-term potentiation (LTP) results from increased number of synaptic AMPARs (Chapter 3), enduring memory could arise from synaptogenesis within memory units (Figure 26-1). This view is supported by a growing body of research demonstrating that the formation of enduring memories is associated with increase of dendritic spines (Restivo et al., 2009; Xu et al., 2009; Yang et al., 2009; Fu et al., 2012; Yang et al., 2014; Keifer et al., 2015; Bello-Medina et al., 2016). In particular, Fu et al. (2012) showed that, during the acquisition phase of repetitive motor learning, a third of new dendritic spines emerge in clusters, and that most such clusters are neighboring spine pairs. Yang et al. (2014) reported that, after motor learning, new spines are formed on different sets of dendritic branches in response to different learning tasks.
The Role of Arc in Memory Erasure and Consolidation
The idea that synaptic AMPARs do not store the enduring memory is further supported by the dual roles of activity-regulated cytoskeletal-associated protein (Arc, also known as Arg3.1). It has been well-documented that Arc promotes long-term depression (LTD) by enhancing AMPAR endocytosis (Chowdhury et al., 2006; Waung et al., 2008; Jakkamsetti et al., 2013; Wilkerson et al., 2018). This function was proposed to reset synaptic strength to a basal level (Rial Verde et al., 2006; Shepherd et al., 2006). On the other hand, Arc also facilitates the formation of long-lasting memory (Guzowski et al., 2000; Plath et al., 2006; Messaoudi et al., 2007; Ploski et al., 2008; Maddox and Schafe, 2011; Holloway and McIntyre, 2011; Morin et al., 2015). The two functions are hard to be reconciled if enduring memory is stored in synaptic AMPARs, but can be explained if enduring memory arises from synaptogenesis.
AMPAR trafficking within spines involves actin cytoskeleton which is regulated by cofilin (Hanley, 2014). Activation of cofilin may lead to depolymerization of actin filaments (F-actin) (Elam et al., 2013). Cofilin activity is directly controlled by the phosphorylation status at Ser-3. Dephosphorylation of Ser-3 results in cofilin activation. Arc has been shown to induce cofilin phosphorylation, making it inactive (Messaoudi et al., 2007). Therefore, Arc acts to suppress F-actin depolymerization.
While microtubules are responsible for long-range intracellular transport of various cargos (proteins, mRNA, mitochondria, etc), F-actin is important for short range transport in dendrites, including dendritic spines and shafts (Konietzny et al., 2017). Myosin is the major motor protein that drives actin transport. It has several isoforms. Within dendritic spines, the AMPAR internalization is powered by Myosin VI which moves AMPARs from the spine membrane to the endosome, leading to AMPAR internalization (Figure 26-2). Since Arc suppresses F-actin depolymerization, it may provide a stable actin cytoskeleton for the transport of AMPARs. This could be the underlying mechanism for the involvement of Arc in LTD.
Then, how can Arc be involved in memory consolidation? Interestingly, another Myosin isoform, Myosin II, has been demonstrated to be essential for memory consolidation (Gavin et al., 2011; Young et al., 2016). These results suggest that Arc may influence both LTD and memory consolidation through the same function: stabilization of actin cytoskeleton to facilitate trafficking. If enduring memory is stored in synaptic AMPARs, one would assume that Myosin II could drive AMPAR insertion into the spine membrane. However, it has been known that the motor protein that directs AMPAR traffic toward the spine membrane is Myosin V, not Myosin II (Figure 26-2). Instead, Myosin II has been shown to mediate translocation of the stable F-actin (bound by drebrin A) from spines to the dendritic shaft (Mizui et al., 2014). CRMP2, together with tubulin, are proposed to bind the stable F-actin (Chapter 20). They could be transported with F-actin to the dendritic shaft for synaptogenesis (next chapter).
Author: Frank Lee