|Memory > Born to Forget: The Underlying Mechanism|
"Forgetting" may arise from either memory erasure or memory extinction. The memory erasure is due to AMPAR internalization (Chapter 36) whereas memory extinction could result from NMDAR extinction (Chapter 19). Compelling evidence suggests that some memory acquired in wake could be erased in sleep, as reflected in the decrease of synaptic AMPARs during sleep (Tononi and Cirelli, 2014). This chapter aims to elucidate how sleep promotes both memory erasure and extinction.
How Sleep Promotes AMPAR Internalization
Calcineurin (CaN) is upregulated during sleep (Cirelli et al., 2004). This enzyme plays a key role in AMPAR internalization. Its activity depends on Ca2+. In the resting state, CaN is anchored to GluN2B-containing NMDARs via AKAP79/150. When the subject is awake, prolonged low frequency sensory inputs may open GluN2B-NMDARs, allowing the Ca2+ influx to efficiently activate CaN, thereby resulting in its dissociation from AKAP79/150. Subsequently, CaN may dephosphorylate the GluA1 subunit of AMPARs at S845, leading to AMPAR internalization (see Chapter 18 and Chapter 36).
During slow wave sleep, there is no sensory input. However, the GluN2B-NMDARs can be opened by the glutamate released from astrocytes, provided that the NMDAR extinction has been recovered. In deep sleep, the NMDAR extinction is recovered by norepinephrine which controls the UP and DOWN states of slow oscillations (Chapter 34).
Targeting of Homer1a to the postsynaptic density (PSD) also increases during sleep (Diering et al., 2017). Homer1 plays an important role in synaptic plasticity by regulating group I metabotropic glutamate receptors mGluR1/5. Its variant, Homer1L, links mGluR5 to IP3 receptor (IP3R) to facilitate IP3-mediated release of Ca2+ from intracellular stores (endoplasmic reticulum). Another variant, Homer1a, uncouples mGluR5 from IP3R (Diering et al., 2017), which may lead to AMPAR internalization by reducing tyrosine phosphorylation of GluA2 (Hu et al., 2010). Therefore, during sleep, the increased localization of Homer1a to PSD also promotes AMPAR internalization.
The above results suggest that the default physiological process in sleep is to erase the memory acquired in wake. 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.
How Sleep Promotes Memory Extinction
The upregulation of CaN during sleep also promotes memory extinction. Activation of CaN by Ca2+ may stimulate cofilin to depolymerize F-actin (Wang et al., 2005), causing CABT to switch binding partner from the dynamic F-actin to GluN2B-containing NMDARs, consequently resulting in NMDAR extinction (Chapter 20). In addition, CaN may activate the transcription factor, nuclear factor of activated T-cells (NFAT), which targets the key player in long-term memory extinction: BDNF (Chapter 19 and Chapter 22).
While the erased memory is gone forever, the extinguished memory can be retrieved by (1) recovery from NMDAR extinction, and (2) a substantial glutamate pond. The next chapter will show that the two conditions can be met in the absence of oxygen supply, leading to a well-documented near-death experience: life review.
Author: Frank Lee