Geon The General Mechanism of Memory Extinction and Retrieval Memory

 

Chapter 15 proposes that memory extinction and retrieval could be fundamentally governed by calcineurin (CaN, also known as PP2B) and protein kinase A (PKA), competing for the phosphorylation state of S1166 in NR2B (GluN2B). Phosphorylation of S1166 by PKA facilitates retrieval whereas dephosphorylation of S1166 by CaN promotes extinction, as the dephosphorylated state allows tubulin to bind to the NR2B-containing NMDARs, consequently inhibiting their opening and suppressing neuronal firing. Further details are described in this chapter.

The Role of AKAP79/150

A-kinase anchoring protein 79 (AKAP79) is a human scaffold protein that organizes PKA, CaN and protein kinase C (PKC) at a specific subcellular location to restrict their substrate targeting. For instance, the PKA anchored to a synaptic AMPA receptor (AMPAR) should be more effective in phosphorylating the AMPAR than the PKA diffusing randomly in the cytoplasm. AKAP79, together with anchored proteins, can be recruited to the postsynaptic membrane via membrane-associated guanylate kinase (MAGUK) scaffolding proteins such as PSD-95 and SAP97 (Dai et al., 2009, Figure 10; Sanderson and Dell'Acqua, 2011).

The human AKAP79 is homologous to AKAP150 (also called AKAP5) in rodents. They have similar functions. Experimental studies have established that the AKAP79/150 anchored to synaptic AMPARs plays a pivotal role in long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are fundamentally controlled by synaptic retention and endocytosis of AMPARs, respectively. This in turn depends on the phosphorylation status of S845, S831 and S818 in the GluR1 subunit of AMPARs (Sanderson and Dell'Acqua, 2011; Woolfrey and Dell'Acqua, 2015; Sanderson et al., 2016). S845 is the target of both PKA and CaN while S831 and S818 can be phosphorylated by CaMKII and PKC. Dephosphorylation of S845 by CaN promotes LTD, but phosphorylation of S845 by PKA is implicated in both LTP and LTD.

While the anchoring of AKAP79/150 to AMPARs for the regulation of LTP and LTD has been well established, the association between AKAP79/150 and NMDARs is less clear. The C- termini of NR2 subunits bind to PSD-95, which can interact with AKAP150, but it is unclear whether PSD-95 recruits AKAP150 to NMDARs (Dai et al., 2009). The present model suggests that AKAP79/150 could be recruited to NR2B-, but not NR2A-containing NMDARs so that the anchored PKA and CaN may regulate memory extinction and retrieval in the following manner.

The Extinction Mechanism

PKA is also known as "cAMP-dependent protein kinase" because its activity depends on the binding of cyclic AMP (cAMP). In the resting state, NMDARs are phosphorylated (presumably at S1166 of NR2B) by basally active PKA (Raman et al., 1996). During excitatory transmission, the Ca2+ influx through NR2B-containing NMDARs may stimulate CaN, resulting in S1166 dephosphorylation, which would allow tubulin to bind to the NR2B-containing NMDARs, thereby leading to extinction. The extinction process may take 5 - 15 minutes, as manifested in the short-term potentiation (Chapter 14). 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

According to the fundamental postulate proposed in Chapter 7, the retrieval of extinction memory requires dissociation of tubulin from NMDARs. This implies that the phosphorylation of S1166 by PKA can facilitate memory retrieval. A number of studies have provided evidence for the critical role of PKA in memory retrieval:

  1. Disruption of PKA anchoring to AKAP proteins promotes extinction of contextual fear memories (Nijholt et al., 2008).
  2. The activators of PKA block fear extinction (Corcoran et al., 2015).
  3. The NR2B-mediated PKA inhibition prevents retrieval of remote memory (Corcoran et al., 2013).
  4. Norepinephrine promotes retrieval via the stimulation of β1-adrenergic receptors (β1ARs) (Zhang et al., 2013).
  5. Blockade of the M1 type muscarinic acetylcholine receptors (M1-AChRs) impairs the retrieval of well-trained memory (Soma et al., 2016).
  6. The serotonin 2A receptors (5-HT2ARs) control the retrieval of recognition memory in rats (Bekinschtein et al., 2013).

Activation of β1ARs, M1-AChRs or 5-HT2ARs may trigger signaling cascades to activate PKA. Details are discussed in subsequent chapters.

Summary

Image

Figure 16-1. The proposed mechanism of memory extinction and retrieval.
(1) In the resting state, S1166 of NR2B is phosphorylated by PKA, preventing NMDAR inhibition by tubulin.
(2) The Ca2+ influx through NR2B-containing NMDARs may activate calcineurin to dephosphorylate S1166.
(3) S1166 dephosphorylation allows NMDAR inhibition by tubulin.
(4) Neurotransmitters, such as norepinephrine, acetylcholine and serotonin, may trigger signaling cascades to activate PKA, resulting in S1166 phosphorylation, consequently leading to the dissociation of tubulin from NMDARs.

 

Author: Frank Lee
First published: November, 2017