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

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 (Chapter 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).

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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.

 

Author: Frank Lee
First published: July, 2018