Abstract:It has been shown that a variety of long-term memories in different regions of the brain and in different species are quickly erased by local inhibition of protein kinase Mζ (PKMζ), a persistently active protein kinase. Using antibodies to mammalian PKMζ, we describe in the present study the localization of immunoreactive molecules in the nervous system of the terrestrial snail Helix lucorum. Presence of a homolog of PKMζ was confirmed with transcriptomics. We have demonstrated in behavioral experiments that c… Show more
“…We note that Volk et al had reported ZIP induces decreases in both tetanized and untetanized pathways in slices ( Volk et al, 2013 ). These results conflict with evidence from a large number of studies showing exclusive actions of ZIP in tetanized or facilitated pathways and not in baseline pathways, including seven studies in brain slices of fEPSPs ( Ling et al, 2002 ; Serrano et al, 2005 ; Sajikumar et al, 2005 ; Navakkode et al, 2010 ; Lin et al, 2012 ; Panaccione et al, 2013 ; Chen et al, 2015 ), four studies of EPSCs ( Li et al, 2010 ; Yao et al, 2013 ; Velez-Hernandez et al, 2013 ; Li et al, 2014 ), two studies in model systems ( Cai et al, 2011 ; Balaban et al, 2015 ), and four studies in vivo of fEPSPs ( Pastalkova et al, 2006 ; Madronal et al, 2010 ; Dong et al, 2015 ) and evoked responses ( Cooke and Bear, 2010 ), as well as evidence of stable basal properties of hippocampal neurons following ZIP injections recorded in vivo ( Barry et al, 2012 ). DOI: http://dx.doi.org/10.7554/eLife.14846.004 10.7554/eLife.14846.005 Figure 1—figure supplement 2.…”
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI:
http://dx.doi.org/10.7554/eLife.14846.001
“…We note that Volk et al had reported ZIP induces decreases in both tetanized and untetanized pathways in slices ( Volk et al, 2013 ). These results conflict with evidence from a large number of studies showing exclusive actions of ZIP in tetanized or facilitated pathways and not in baseline pathways, including seven studies in brain slices of fEPSPs ( Ling et al, 2002 ; Serrano et al, 2005 ; Sajikumar et al, 2005 ; Navakkode et al, 2010 ; Lin et al, 2012 ; Panaccione et al, 2013 ; Chen et al, 2015 ), four studies of EPSCs ( Li et al, 2010 ; Yao et al, 2013 ; Velez-Hernandez et al, 2013 ; Li et al, 2014 ), two studies in model systems ( Cai et al, 2011 ; Balaban et al, 2015 ), and four studies in vivo of fEPSPs ( Pastalkova et al, 2006 ; Madronal et al, 2010 ; Dong et al, 2015 ) and evoked responses ( Cooke and Bear, 2010 ), as well as evidence of stable basal properties of hippocampal neurons following ZIP injections recorded in vivo ( Barry et al, 2012 ). DOI: http://dx.doi.org/10.7554/eLife.14846.004 10.7554/eLife.14846.005 Figure 1—figure supplement 2.…”
PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings. First, PKMζ is unimportant for LTP or memory. Second, PKMζ is essential for late-LTP and long-term memory in wild-type mice, and PKMζ-null mice recruit compensatory mechanisms. We find that whereas PKMζ persistently increases in LTP maintenance in wild-type mice, PKCι/λ, a gene-product closely related to PKMζ, persistently increases in LTP maintenance in PKMζ-null mice. Using a pharmacogenetic approach, we find PKMζ-antisense in hippocampus blocks late-LTP and spatial long-term memory in wild-type mice, but not in PKMζ-null mice without the target mRNA. Conversely, a PKCι/λ-antagonist disrupts late-LTP and spatial memory in PKMζ-null mice but not in wild-type mice. Thus, whereas PKMζ is essential for wild-type LTP and long-term memory, persistent PKCι/λ activation compensates for PKMζ loss in PKMζ-null mice.DOI:
http://dx.doi.org/10.7554/eLife.14846.001
“…This eliminates a controversy with data indicating that PKMζ may be not crucial for memory maintenance ( Lee et al, 2013 ; Volk et al, 2013 ). Additional evidence of PKMζ necessity for memory storage in invertebrates has been published recently ( Balaban et al, 2015 ) and its role in memory has been shown without inhibitors, using the effect of PKMζ overexpression in the hippocampus on behavior and LTP in rats ( Schuette et al, 2016 ).…”
For protein synthesis that occurs locally in dendrites, the translational control mechanisms are much more important for neuronal functioning than the transcription levels. Here, we show that uORFs (upstream open reading frames) in the 5′ untranslated region (5′UTR) play a critical role in regulation of the translation of protein kinase Mζ (PKMζ). Elimination of these uORFs activates translation of the reporter protein in vitro and in primary cultures of rat hippocampal neurons. Using cell-free translation systems, we demonstrate that translational initiation complexes are formed only on uORFs. Further, we address the mechanism of translational repression of PKMζ translation, by uORFs. We observed an increase in translation of the reporter protein under the control of PKMζ leader in neuronal culture during non-specific activation by picrotoxin. We also show that such a mechanism is similar to the mechanism seen in cell stress, as application of sodium arsenite to neuron cultures induced translation of mRNA carrying PKMζ 5′UTR similarly to picrotoxin activation. Therefore, we suppose that phosphorylation of eIF2a, like in cell stress, is a main regulator of PKMζ translation. Altogether, our findings considerably extend our understanding of the role of uORF in regulation of PKMζ translation in activated neurons, important at early stages of LTP.
“…This idea is based on the following data: Long-term potentiation and memory are accompanied by increasing of the PKMζ protein level in memory-associated structures [ 79 , 80 , 81 , 82 ]; PKMζ inhibitor ZIP erases established memory in mammals and invertebrates [ 73 , 74 , 75 , 82 , 83 ]; PKMζ inhibitor ZIP disrupts the late phase of long-term potentiation, a cellular model of synaptic plasticity and memory [ 72 , 81 , 84 ]; Knockdown of PKMζ in the hippocampus impairs long-term potentiation and negatively regulates memory maintenance [ 85 , 86 ]; Overexpression of PKMζ enhances memory [ 87 , 88 , 89 ]. …”
Section: Protein Kinase Mζ Its Functions and Regulation Of Its Trmentioning
Compared to other types of cells, neurons express the largest number of diverse mRNAs, including neuron-specific ones. This mRNA diversity is required for neuronal function, memory storage, maintenance and retrieval. Regulation of translation in neurons is very complicated and involves various proteins. Some proteins, implementing translational control in other cell types, are used by neurons for synaptic plasticity. In this review, we discuss the neuron-specific activity of four kinases: protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control nonderepressible 2 kinase (GCN2), and heme-reguated eIF2α kinase (HRI), the substrate for which is α-subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α is necessary for the cell during stress conditions, such as lack of amino acids, energy stress or viral infection. We propose that, during memory formation, neurons use some mechanisms similar to those involved in the cellular stress. The four eIF2α kinases regulate translation of certain mRNAs containing upstream open reading frames (uORFs). These mRNAs encode proteins involved in the processes of long-term potentiation (LTP) or long-term depression (LTD). The review examines some neuronal proteins for which translation regulation by eIF2 was suggested and checked experimentally. Of such proteins, we pay close attention to protein kinase Mζ, which is involved in memory storage and regulated at the translational level.
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