|Transitional Memory: PKMζ and PKCι/λ||Memory|
The following is one of two fundamental postulates proposed in Chapter 7:
"Memory extinction occurs when the amount of synaptic AMPARs remains elevated, but NMDARs are inhibited by tubulin."
How can synaptic AMPARs remain elevated? The constitutive endocytosis will reduce the number of AMPARs on the postsynaptic membrane (Chapter 4). To maintain synaptic AMPARs at a high level, other mechanisms must at work. Over the past two decades, the Sacktor's lab has provided compelling evidence that PKMζ and PKCι/λ play key roles in memory maintenance (Ling et al., 2002; Sacktor, 2012; Tsokas et al., 2016).
Memory Maintenance by PKMζ and PKCι/λ
PKMζ is a persistently active protein kinase. Once synthesized at the synapse, the active PKMζ may upregulate the GluA2-containing AMPARs by decreasing receptor endocytosis mediated by N-ethylmaleimide-sensitive factor (NSF) (Figure 9-1). Furthermore, PKMζ can also phosphorylate the palmitoylation enzyme ZDHHC8, promoting the trafficking of PSD-95 and AMPARs to dendritic spines (Yoshii et al., 2011; Thomas et al., 2012). Both PSD-95 and AMPARs are the essential components of spines, consistent with the finding that ZDHHC8 deficiency reduces the spine density (Mukai et al., 2008).
By 2012, the mechanisms underlying the function of PKMζ in memory retention have been largely unveiled. Unexpectedly, in 2013, two independent groups reported that knockout of the gene encoding PKMζ did not have any significant impact on learning and memory (Lee et al., 2013; Volk et al., 2013). This appeared to be a serious blow to the Sacktor's group. Fortunately, it turns out that another closely related protein kinase, PKCι/λ, may compensate for the function of PKMζ (Tsokas et al., 2016). Both PKMζ and PKCι/λ can be inhibited by the zeta inhibitory peptide (ZIP). When ZIP was injected into the hippocampus after learning, both enzymes were inhibited and the learning-induced memory was impaired. However, if only the PKMζ gene was deleted, PKCι/λ can still take over the functions of PKMζ.
This situation is similar to CRMP2, which the present book posits to play a key role in memory extinction and retrieval. The antibody against CRMP2 has been demonstrated to induce amnesia (Mileusnic and Rose, 2011), but deletion of the CRMP2 gene causes only mild memory impairment (Nakamura et al., 2016; Zhang et al., 2016). The CRMP family includes five members (Schmidt and Strittmatter, 2007). Other members are likely to compensate for the loss of CRMP2, whereas the anti-CRMP2 antibody may also render other CRMP members dysfunctional.
Comparison to Phosphorylation of CaMKII at T305/T306
As mentioned briefly in Chapter 6, the phosphorylation of CaMKII at T305/T306 can also stabilize the synaptic AMPARs at an elevated level. Further studies shows that it is due to the reduction of proteasomal degradation of AMPARs in synapses (Naskar et al., 2014). The two pathways have a major difference: while PKMζ and PKCι/λ maintain GluA2-containing AMPARs at the synapse, the T305/T306 phosphorylated CaMKII maintains GluA1-containing AMPARs. An AMPAR consists of four subunits, each could be one of four different types: GluA1, GluA2, GluA3 and GluA4. Most AMPARs contain GluA2, which renders the channel impermeable to Ca2+. The lack of GluA2 allows both Ca2+ and Na+ ions to pass through. Therefore, the T305/T306 phosphorylated CaMKII would maintain Ca2+-permeable AMPARs (CP-AMPARs), but PKMζ and PKCι/λ maintain Ca2+-impermeable AMPARs. These two classes of AMPARs have profound difference in memory retrieval.
The Transitional Memory
In the literature, the term "long-term memory" usually refers to the memory that can last longer than one day. However, there is a clear difference between the memories that exist less than a month and those that last much longer. In this book, the former will be called "transitional memory" and the latter "very long-term memory". The transitional memory is the memory being "consolidated". It could be eliminated or converted into very long-term memory.
Both PKMζ and PKCι/λ are responsible for transitional memory, not very long-term memory. Experiments have demonstrated that their inhibitor, ZIP, could impair the learning-induced memory if applied a few days after learning, but had no effect if applied two weeks or a month later (Parsons and Davis, 2011; Hales et al., 2015). These results suggest that the major function of PKMζ and PKCι/λ is to maintain an adequate level of synaptic AMPARs while the memory is being consolidated. Once the transitional memory has been converted into very long-term memory, PKMζ and PKCι/λ will no longer have any effect. Then, what is the physical memory traces of the very long-term memory? This question will be discussed in a later chapter.
Author: Frank Lee