|The General Mechanism of Memory Extinction and Retrieval||Memory|
Memory extinction refers to the state of a memory in which the physical memory traces of the memory still exist but could not be retrieved at a given moment. If the memory traces have gone forever, the memory is said to be "erased". Chapter 13 have arrived at the following conclusion:
Further details are described in this chapter.
The Microscopic States
The macroscopic memory state results from the microscopic states of NMDARs that give rise to NMDA plateaus. Regarding memory extinction and retrieval, a GluN2B-containing NMDAR can have three distinct states.
The GluN2A-containing NMDAR does not have the extinction state, because the tubulin/CRMP2 complex binds only to GluN2B, not GluN2A. Therefore, the macroscopic memory extinction should depend on the GluN2B/GluN2A ratio in the dendritic branches that encode the memory. A large GluN2B/GluN2A ratio is prone to memory extinction.
The Extinction Mechanism
In the resting state, NMDARs are phosphorylated (presumably at S1166 of GluN2B) by basally active PKA (Raman et al., 1996). This region is assumed to be the binding site of tubulin - a highly negatively charged protein. Since phosphorylation is a process that adds a negatively charged phosphate group PO43- to a protein, it should prevent tubulin binding at this region. Therefore, tubulin does not have any effect on the NMDAR opening or extinction when S1166 is phosphorylated.
During excitatory transmission, the Ca2+ influx through GluN2B-containing NMDARs may stimulate the CaN anchored to GluN2B via AKAP79/150 (Chapter 18), resulting in S1166 dephosphorylation, which would allow tubulin to bind to the GluN2B-containing NMDARs, leading to extinction. The extinction process may take 5 - 15 minutes, as manifested in the decline of short-term potentiation (Chapter 16). In contrast, the desensitization process reflected in the falling phase of NMDAR currents during agonist binding takes less than a second (Erreger et al., 2005).
The Retrieval Mechanism
As mentioned above, phosphorylation of S1166 by PKA facilitates retrieval, because it can cause dissociation of tubulin from GluN2B. The activity of PKA depends on the binding of cyclic AMP (cAMP), whose level is regulated by adenylyl cyclase (AC) that can catalyze the conversion from ATP to cAMP. The activity of AC is under the regulation of various pathways. For instance, norepinephrine may bind to the β1 adrenergic receptors, triggering G-protein-coupled signaling to enhance AC activity (Chapter 21). On the other hand, the AC subtype 1 (AC1) can also be activated by calcium-calmodulin (Wong et al., 1999), thereby promoting PKA activity. Hence, AC1 provides a convenient pathway for Ca2+ to increase PKA activity. This pathway is very important as PKA is anchored to GluN2B via AKAP79/150 (Chapter 18), permitting the Ca2+ influx through GluN2B-containing NMDARs to efficiently activate PKA and augment long-term potentiation (LTP). This also explains why AC1 contributes to LTP in the neocortex of adult mice (Chen et al., 2014; Yamanaka et al., 2017).
A number of studies have provided evidence for the critical role of PKA in memory retrieval:
Activation of M1-AChRs may trigger signaling cascades to increase Ca2+ level, consequently activating PKA. Details will be discussed in a later chapter.
Author: Frank Lee