Atypical PKCs in memory maintenance: the roles of feedback and redundancy

Abstract

Memories that last a lifetime are thought to be stored, at least in part, as persistent enhancement of the strength of particular synapses. The synaptic mechanism of these persistent changes, late long-term potentiation (L-LTP), depends on the state and number of specific synaptic proteins. Synaptic proteins, however, have limited dwell times due to molecular turnover and diffusion, leading to a fundamental question: how can this transient molecular machinery store memories lasting a lifetime? Because the persistent changes in efficacy are synapse-specific, the underlying molecular mechanisms must to a degree reside locally in synapses. Extensive experimental evidence points to atypical protein kinase C (aPKC) isoforms as key components involved in memory maintenance. Furthermore, it is evident that establishing long-term memory requires new protein synthesis. However, a comprehensive model has not been developed describing how these components work to preserve synaptic efficacies over time. We propose a molecular model that can account for key empirical properties of L-LTP, including its protein synthesis dependence, dependence on aPKCs, and synapse-specificity. Simulations and empirical data suggest that either of the two aPKC subtypes in hippocampal neurons, PKMz and PKCi/l, can maintain L-LTP, making the system more robust. Given genetic compensation at the level of synthesis of these PKC subtypes as in knockout mice, this system is able to maintain L-LTP and memory when one of the pathways is eliminated.

ZIP It: Neural Silencing Is an Additional Effect of the PKM-Zeta Inhibitor Zeta-Inhibitory Peptide

“…Although prior studies have implied that ZIP does not impair spontaneous or evoked network activity, these studies only reported data for time windows beyond 2 h after infusion (Madroñal et al, 2010;Barry et al, 2012). Our study demonstrates significant inhibition of local network activity within that time frame.…”

“…This timing is similar to the suppressive effect of anisomycin (Sharma et al, 2012), but slower than agents acting directly on ion channels (present study and van Duuren et al, 2007), which suggests that it acts via a (yet unknown) biochemical signaling mechanism. Furthermore, the presence of epileptiform activity after ZIP administration in seven of 12 (ϳ60%) of our ZIP experiments (despite the fact that urethane anesthesia is known to dampen seizure activity; Cain et al, 1989) presents additional interpretational problems for prior studies. For example, although ZIP was suggested to interfere with place cell stability (Barry et al, 2012), electrophysiological data were only reported after at least a 2 h period after ZIP administration.…”

“…Furthermore, the presence of epileptiform activity after ZIP administration in seven of 12 (ϳ60%) of our ZIP experiments (despite the fact that urethane anesthesia is known to dampen seizure activity; Cain et al, 1989) presents additional interpretational problems for prior studies. For example, although ZIP was suggested to interfere with place cell stability (Barry et al, 2012), electrophysiological data were only reported after at least a 2 h period after ZIP administration. In the absence of clear neurophysiological data within this time frame, it is difficult to eliminate the possibility of an activity-modulating influence of ZIP, especially because it is known that epileptic activity can cause remapping of place cells (Zhou et al, 2007).…”

“…Indeed, a marked and lasting decrease in LFP activity comparable in magnitude with-although delayed in latency and longer lasting than-infusion of 4% lidocaine was observed. Given that intrahippocampal infusions of lidocaine before retention testing produce memory deficits in hippocampal-dependent tasks such as the Morris water maze (Bohbot et al, 1996;Broadbent et al, 2006), we propose that experiments in which ZIP is similarly infused just before retention testing (the most common protocol used; Kwapis and Helmstetter, 2014) may produce memory deficits due to its detrimental influence on neural activity as opposed to any specific effect on PMK. Indeed, neural inactivation (or even epileptic disruption, as we also observed) after ZIP administration may have detrimental effects on memory measures beyond the normal 2 h post-ZIP application retention test.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…This inhibitor may not be specific for PKMz, and genetic inactivation models of PKMz activity have failed to alter memory processes that were suggested to be dependent on PKMz (Lee et al, 2013a;Volk et al, 2013). Other atypical PKC members might compensate the genetic inactivation of PKMz, suggesting redundance of regulating mechanisms (Jalil et al, 2015).…”