Persistent increases of PKMζ in memory‐activated neurons trace LTP maintenance during spatial long‐term memory storage

Abstract

PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain. Using quantitative immunohistochemistry validated by the lack of staining in PKMζ-null mice, we examined the amount and distribution of PKMζ in subregions of the hippocampal formation of wild-type mice during LTP maintenance and spatial long-term memory storage. During LTP maintenance in hippocampal slices, PKMζ increases in the pyramidal cell body and stimulated dendritic layers of CA1 for at least 2 hr. During spatial memory storage, PKMζ increases in CA1 pyramidal cells for at least 1 month, paralleling the persistence of the memory. During the initial expression of the memory, we tagged principal cells with immediate-early gene Arc promoterdriven transcription of fluorescent proteins. The subset of memory-tagged CA1 cells selectively increases expression of PKMζ during memory storage, and the increase persists in dendritic compartments within stratum radiatum for 1 month, indicating long-term storage of information in the CA3-to-CA1 pathway. We conclude that persistent increases in PKMζ trace the molecular mechanism of LTP maintenance and thus the sites of information storage within brain circuitry during long-term memory.

Learning to learn persistently modifies an entorhinal-hippocampal excitatory-inhibitory subcircuit

“…The CCT-induced, persistent changes in entorhinal-hippocampus circuit function demonstrate that appropriately structured cognitive experiences can persistently change information processing within neural subcircuits. As such, the present findings strongly support the neuroplasticity hypothesis, although of course, CCT causes additional changes 14,17,47 , with others yet to be discovered. Prior work showed that preemptive CCT in adolescence prevented cognitive impairment due to neonatal neurodevelopmental brain damage 48 , and as also demonstrated here, mere place learning was not sufficient to cause several neurobiological changes that CCT causes.…”

“…This neural network motif will also stabilize the connection's inputoutput relationship 37,38 . Similar disinhibitory plasticity has also been described at the Schaffer collateral and other cortical synapses [39][40][41] , where CCT causes persistent increased expression of PKMz, which is itself necessary and sufficient for maintaining LTP 17,42 . The CCT-induced subcircuit changes were detected in field potential recordings, indicating they are not the sparse changes that mediate content-specific memory formation that the synaptic plasticity and memory hypothesis predicts 43 .…”

“…We exploited an experimental platform that demonstrated persistent ex vivo and anesthetized in vivo electrophysiological changes in GABAergic-sensitive hippocampus synaptic function after learning an active place avoidance task 14 . The task requires intact hippocampal activity 15,16 , and persistent PKMzeta (PKMζ)-mediated long-term potentiation (LTP) of hippocampal synaptic function [17][18][19][20] .…”

Conditions for Synaptic Specificity during the Maintenance Phase of Synaptic Plasticity

“…We have argued that such a switch is most likely implemented at the level of translation, and that the synthesized protein that potentiates synaptic transmission is PKM ζ . The approach we take is based on the observation that its synthesis is likely local in dendrites and perhaps spines ( Muslimov et al, 2004 ; Westmark et al, 2010 ; Palida et al, 2015 ), and that the induction of L-LTP results in a local and sustained increase of PKM ζ in spines ( Hsieh et al, 2021 ). The synthesis of a specific protein (for example, PKM ζ ) could affect its own level of translation, and this positive feedback loop can generate bistable or multstable switches ( Westmark et al, 2010 ).…”

Introducing the special issue on “Proteins and Circuits in Memory”

“…Once synthesized in response to synaptic stimulation, the kinase PKMζ remains persistently active in the absence of further stimuli, which is key to the maintenance of LTP (Sacktor & Fenton, 2018). Here, Hsieh et al (2021) use quantitative immunohistochemistry to study the upregulation of PKMζ in synapses encoding active place avoidance. PKMζ levels increase for at least a month and increases with neurons in the CA1, where the Arc promotor was activated.…”