|Memory > Memory Consolidation: The Role of PKMζ|
PKMζ is an atypical protein kinase C (aPKC). Once synthesized, the enzyne is persistently active. With this property, PKMζ was thought to maintain both long-term potentiation (LTP) and enduring memory (> 1 month) (Sacktor, 2012). This hypothesis was based on the findings that disruption of PKMζ activity by zeta inhibitory peptide (ZIP), genetic knockdown, or antisense oligonucleotide, impaired the formation of enduring memory (Shema et al., 2007; Wang et al., 2016; Yu et al., 2017). The PKMζ disruption was usually introduced in less than a month after training Hsieh et al., 2017. A recent study, however, demonstrated that ZIP could impair the learning-induced memory if applied a few days after learning, but had no effect if applied two weeks or a month later (Hales et al., 2015; Hales et al., 2016).
Effects of PKMζ on Synaptic AMPARs
PKMζ has the capacity to retain high level of synaptic AMPA receptors (AMPARs), which underlies the mechanism of LTP. After being produced near the synapse, the active PKMζ may up-regulate GluA2-containing AMPARs by decreasing receptor endocytosis mediated by N-ethylmaleimide-sensitive factor (NSF) (Figure 29-1). In addition, PKMζ may impede lateral movement of GluA2-containing AMPARs at the synapse, thereby increasing synaptic AMPARs (Yu et al., 2017). However, as pointed out in Chapter 26, enduring memory could arise from synaptogenesis within memory units, rather than the persistence of elevated synaptic AMPARs.
After LTP induction, the activity-regulated cytoskeletal-associated protein (Arc, also known as Arg3.1) is rapidly upregulated. Surprisingly, Arc promotes long-term depression (LTD) by enhancing AMPAR endocytosis (Chowdhury et al., 2006; Waung et al., 2008; Jakkamsetti et al., 2013; Wilkerson et al., 2018). This function was proposed to reset synaptic strength to a basal level (Rial Verde et al., 2006; Shepherd et al., 2006). It may play an important role in erasing trivial memories. In addition, during sleep, calcineurin and Homer1a are upregulated to promote AMPAR internalization (Chapter 37), suggesting that the default physiological process is to maintain synaptic strength at a basal level. To strengthen some memories, the learning-potentiated memory units should generate new synapses. This requires repetitive stimulation of the memory units to facilitate spine growth. During the consolidation period, PKMζ may be necessary to maintain a high level of synaptic AMPARs, countering the action of calcineurin and Homer1a. However, after the consolidation is complete, PKMζ becomes dispensable, as observed by Hales et al. (2015).
Author: Frank Lee