title: 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 Mζ (PKMζ) has been found to be involved in the formation and maintenance of long-term memory. Most of the studies investigating PKMζ, 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 PKMζ in rat hippocampus, a structure highly involved in memory formation, and embedded in several neural networks. We investigated PKMζ'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 PKMζ show enhanced basal transmission, suggesting a potential role of PKMζ in postsynaptic AMPAR trafficking. Moreover, the PKMζ-overexpressing slices augmented LTP and this effect was not abolished by protein-synthesis blockers, indicating that PKMζ induces enhanced LTP formation in a protein-synthesis-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 PKMζ 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 PKMζ in synaptic plasticity and selective memory processing.
  
  
  CONCLUSIONS
  Most of the literature investigating protein kinase Mζ (PKMζ) used inhibitors with selectivity that has been called into question or conventional knock-out animal models in which compensatory mechanisms may occur. To avoid these issues, some studies have been done using viral overexpression of PKMζ in different brain structures to show cognitive enhancement. However, electrophysiological experiments were exclusively done in knock-out models or inhibitory studies to show depletion of LTP. There was no study showing the effect of PKMζ overexpression in the hippocampus on behavior and LTP experiments. To our knowledge, this is the first study to combine these aspects with the result of enhanced memory for contextual fear memory and to show enhanced LTP in hippocampal slices overexpressing PKMζ.
authors.affiliation: CNS Research and sven.schuette@boehringer-ingelheim.com scott.hobson@boehringer-ingelheim.com.
authors.forename: Sven R M
authors.identifier: http://orcid.org/0000-0003-3987-6838
authors.initials: SR
authors.lastname: Schuette
authors.affiliation: CNS Research and.
authors.forename: Diego
authors.initials: D
authors.lastname: Fernández-Fernández
authors.affiliation: Target Discovery Research, Boehringer Ingelheim Pharma, 88397 Biberach a.d. Riss, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lamla
authors.affiliation: CNS Research and.
authors.forename: Holger
authors.initials: H
authors.lastname: Rosenbrock
authors.affiliation: CNS Research and sven.schuette@boehringer-ingelheim.com scott.hobson@boehringer-ingelheim.com.
authors.forename: Scott
authors.initials: S
authors.lastname: Hobson
mesh_terms: D000818:Animals; D003216:Conditioning, Operant; D003463:Cues; D005239:Fear / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics / Q000502:physiology; D005822:Genetic Vectors; D006624:Hippocampus / Q000201:enzymology* / Q000502:physiology*; D017774:Long-Term Potentiation / Q000235:genetics*; D008297:Male; D008568:Memory / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009949:Orientation / Q000502:physiology; D011493:Protein Kinase C / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D065852:Spatial Memory / Q000502:physiology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology
chemical_list: D011500:Protein Synthesis Inhibitors; D018091:Receptors, AMPA; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat
keywords: LTP; PKMζ; contextual fear; hippocampus; memory; overexpression