The Role of de novo Synthesis of PKMζ in Dorsal Hippocampus during Long-term Potentiation and Spatial Memory Storage.

Abstract

Protein kinase Mζ (PKMζ) is an autonomously active PKC isoform that plays a key role in long-term memory (LTM) storage. Postsynaptic perfusion of PKMζ causes an increase in the amplitude of EPSCs recorded from CA1 pyramidal cells (Ling, Benardo, & Sacktor, 2006), and overexpression of PKMζ in the neocortex enhances the LTM of conditioned taste aversion (Shema et al., 2011). In addition, inhibition of PKMζ by selective ζ-pseudosubstrate inhibitory peptide (ZIP) reverses the late phase of long-term potentiation (late-LTP) (Serrano, Yao, & Sacktor, 2005; Pastalkova et al., 2006), and disrupts the maintenance of spatial LTM (Pastalkova, et al., 2006; Serrano et al., 2008). However, little is known about the localization of the changes in PKMζ expression after spatial training. Moreover, because ZIP inhibits the enzymatic activity of PKMζ including that of both newly synthesized and pre-existing pools of the kinase, it is not clear which of the two pools mediates the effects of PKMζ on LTM and late-LTP. To address these questions, the localization of the change of PKMζ distribution 24 hr after both massed and spaced training of active place avoidance by immunohistochemistry was first investigated, and the results showed that the increased PKMζ mainly located in stratum pyramidale, radiatum and lacunosum-moleculare in hippocampal CA1 region. This pattern of increased PKMζ persisted 1 month after spaced training. The intracranial injection of PKMζ antisense oligodeoxynucleotides to this area to selectively inhibit de novo PKMζ synthesis was then conducted. The results showed that the antisense injection did not affect the basal level of PKMζ but blocked the increased PKMζ after LTP-inducing tetani or behavioral training. Furthermore, the antisense also disrupted the late-LTP and spatial LTM without affecting early-LTP and short-term memory. The results suggest that de novo synthesis of PKMζ is required for the newly formed LTP and LTM.