คาสิโนไทย Memory Consolidation:
NMDAR Extinction may Cause the DOWN State
Memory

 

At the onset of the UP state, the CABT complexes do not occlude the channel pore of GluN2B-containing NMDARs. They could bind to actin filaments (F-actin). Then, the Ca2+ influx during the UP state may activate cofilin to depolymerize F-actin, resulting in the dissociation of CABT from F-actin (คาสิโนไทยChapter 20). The dissociated CABT complexes may move toward the membrane-bound NMDARs, but they cannot block GluN2B-NMDARs as long as the S1166 of GluN2B remains phosphorylated by protein kinase A (PKA). The CABT complexes may block NMDARs to silence engram cells only when PKA activity is reduced upon termination of NE stimulation. Therefore, the timing of the DOWN state could be controlled by locus coeruleus (LC) which releases NE to various memory storage areas.

During the DOWN state, the Ca2+ level decreases, so is the activity of cofilin. Hence, the F-actin is re-polymerized, capable of binding CABT. In the next cycle, LC neurons release NE to stimulate PKA activity, resulting in dissociation of CABT from NMDARs. The recovery of NMDAR extinction, together with the glutamate provided by sharp wave ripples (SWRs) and astrocytes, may generate the UP state (Chapter 34).

Image

Figure 35-1. A model for the mechanism of slow oscillations between UP and DOWN states.
(A) At the onset of the UP state, S1166 of the GluN2B subunit is phosphorylated by PKA. CABT binds to F-actin.
(B) During the UP state, the Ca2+ influx may activate cofilin to depolymerize F-actin, resulting in the dissociation of CABT from F-actin. The dissociated CABT complexes may move toward the membrane-bound NMDARs, but they cannot block GluN2B-NMDARs as long as the S1166 of GluN2B remains phosphorylated by PKA.
(C) As the NE release from LC neurons terminates, PKA activity decreases, resulting in S1166 dephosphorylation which allows CABT to block GluN2B-NMDARs, consequently leading to the network DOWN state.
(D) During the DOWN state, the Ca2+ level decreases, so is the activity of cofilin. Hence, the F-actin is re-polymerized, capable of binding CABT. In the next cycle, LC neurons release NE to stimulate PKA activity, causing CABT to switch binding partner from GluN2B to F-actin.

The Ca2+ influx during the UP state may lead to three distinct results:

  1. If Myosin II is activated (Somlyo and Somlyo, 2003), CABT could be transported along the stable F-actin from dendritic spines to the shaft. This process, together with the creation of filopodia, may strengthen memory by establishing a prototype of synapses (Chapter 27 and Chapter 28). Synaptic maturation could be achieved by metabotropic glutamate receptor subtype 5 (mGluR5) which may activate the transcription factor, NF-κB (คาสิโนไทยO'Riordan et al., 2006; de la Fuente et al., 2015; Engelmann and Haenold, 2016).
  2. If calcineurin is activated, the association between AMPA receptors (AMPARs) and AKAP79/150 could be disrupted (Chapter 18). Ca2+ can also activate Myosin VI (Batters et al., 2016) to transport AMPARs along F-actin from the synapse to the endosome for degradation (Hanley, 2014). Thus, activation of both calcineurin and Myosin VI could cause AMPAR internalization. This process may weaken or even erase memory.
  3. When calcineurin is activated, it may stimulate cofilin to depolymerize F-actin (Wang et al., 2005), resulting in NMDAR extinction. In addition, calcineurin may activate the transcription factor, nuclear factor of activated T-cells (NFAT), which targets the key player in long-term memory extinction: BDNF (Chapter 22).

Therefore, during slow oscillations, Ca2+ may strengthen, weaken, or extinguish a particular memory, depending on the activation of the pathways of Myosin II/CABT, calcineurin/Myosin VI, and calcineurin/NFAT, respectively. In sleep, calcineurin is upregulated (คาสิโนไทย), suggesting that the default physiological process is to weaken or extinguish the memory acquired in the awake state. To protect from being erased, the memory should be able to induce the expression of PKMζ during the consolidation period. As discussed in Chapter 29, PKMζ may prevent AMPAR internalization.

 

Author: Frank Lee
First published: July, 2018