Overexpression of Protein Kinase Mζ in the Hippocampus Enhances Long-Term Potentiation and Long-Term Contextual But Not Cued Fear Memory in Rats

Abstract

The persistently active protein kinase M (PKM) has been found to be involved in the formation and maintenance of long-term memory. Most of the studies investigating PKM, however, have used either putatively unselective inhibitors or conventional knock-out animal models in which compensatory mechanisms may occur. Here, we overexpressed an active form of PKM in rat hippocampus, a structure highly involved in memory formation, and embedded in several neural networks. We investigated PKM's influence on synaptic plasticity using electrophysiological recordings of basal transmission, paired pulse facilitation, and LTP and combined this with behavioral cognitive experiments addressing formation and retention of both contextual memory during aversive conditioning and spatial memory during spontaneous exploration. We demonstrate that hippocampal slices overexpressing PKM show enhanced basal transmission, suggesting a potential role of PKM in postsynaptic AMPAR trafficking. Moreover, the PKM-overexpressing slices augmented LTP and this effect was not abolished by protein-synthesis blockers, indicating that PKM induces enhanced LTP formation in a proteinsynthesis-independent manner. In addition, we found selectively enhanced long-term memory for contextual but not cued fear memory, underlining the theory of the hippocampus' involvement in the contextual aspect of aversive reinforced tasks. Memory for spatial orientation during spontaneous exploration remained unaltered, suggesting that PKM may not affect the neural circuits underlying spontaneous tasks that are different from aversive tasks. In this study, using an overexpression strategy as opposed to an inhibitor-based approach, we demonstrate an important modulatory role of PKM in synaptic plasticity and selective memory processing.

PKMζ Inhibition Disrupts Reconsolidation and Erases Object Recognition Memory

“…Data (mean Ϯ SEM) are presented as DI during TR, RA, TEST1, and TEST2, n ϭ 9 per group. upstream PKM to modulate hippocampal AMPAR synaptic insertion, in agreement with findings showing that ORM reconsolidation induces synaptic potentiation in the hippocampus (Clarke et al, 2010) and that BDNF facilitates LTP in the absence of protein synthesis through PKM (Mei et al, 2011;Schuette et al, 2016). Therefore, our results should not be generalized to indicate that all memories are sensitive to PKM inhibition only when reactivated.…”

Criteria for identifying the molecular basis of the engram (CaMKII, PKMzeta)

“…2a ) as expected but that LTP and memory were also increased , contrary to the prediction of occlusion (Fig. 2b, c ) [ 28 ] (for similar effects see [ 26 ]). On the basis of this failure of occlusion, it was concluded that PKM-zeta is not critical for maintenance but is instead a modulator of LTP [ 28 ].…”

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…For long‐term potentiation (LTP) induction, a high‐frequency stimulation (HFS) was used consisting of 100 Hz trains of 1‐s duration repeated five times with a 30‐s inter‐train interval (Schuette, Fernandez‐Fernandez, Lamla, Rosenbrock, & Hobson, ). The stimulus intensity was also set to ≈40% of its asymptotic values.…”