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.
Aversively established contextual fear memory manifests itself in robust freezing behavior, often lasting several weeks or months. Therefore, this approach is amenable to investigate the underlying neural circuitries by lesion or inactivation of specific brain regions or to test efficacy of substances that disrupt either the ability to acquire the association or to retrieve memories. In contrast, investigation of memory enhancement using this technique is time intensive since the non-treated control group naturally forgets the learned association only weeks after acquisition. Pharmacological interventions have been used to overcome this time span by disrupting memory at any time point, however, limiting it a mechanistic model of reversal of impairments instead of studying memory enhancement. Here, we investigated several parameters of the cued and contextual fear conditioning (CFC) protocol such that, while memory acquisition is established, loss of fear association occurs within a shorter time frame, allowing studies of memory enhancement in the context of natural forgetting. We found that three predictive tone-cues, each separated from a 0.3 mA foot shock by an interstimulus interval of 2 s and a pre-exposure to the context enables the investigation of enhanced contextual memory 7 d post training without the necessity of inducing pharmacological lesions.
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