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Long-term stabilization of PKMζ in dendritic spines in vitro and differential PKMζ protein regulation in environmental enrichment in vivo.
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Sacktor, Todd C.
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Spring 2012
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2012-04-24
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Doctoral Dissertation
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The constitutively active Protein kinase C isoform, PKMζ, is both necessary and sufficient for maintaining long-term potentiation (LTP), and is critical for the maintenance of several forms of long-term memory. PKMζmaintains enhanced synaptic function during LTP and long-term memory by retaining GluA2-containing AMPA receptors at the postsynaptic site. Since ZIP inhibition of PKMζirreversibly disrupts longterm synaptic enhancement, we hypothesize that the location of PKMζshould be stable at specific synapses in order for the persistent kinase activity to maintain synapse specific information storage during LTP and memory, and that the stability could potentially be maintained by kinase activity-dependent mechanisms.
In the first study, we examined the stability of PKMζlocalization in dendritic spines of cultured hippocampal neurons and compared that to the rate of movement of PKMζin other compartments of the cell. eGFP-PKMζand eGFP-dnPKMζwere overexpressed in cultured hippocampal neurons and we examined fluorescent PKMζ-fusion protein mobility by fluorescent recovery after photobleaching (FRAP) analysis.
We showed that PKMζprotein mobility in dendritic spines is limited, which may be due to kinase activity-dependent and very tight kinase activity-independent protein interactions. We speculate that immobilization of PKMζin the dendritic spine through
tight protein interactions may be what keeps PKMζstable at specific synapses to
maintain long-lasting synaptic efficacy in vivo.
PKMζplays other roles in brain plasticity. During brain development PKMζ activity affects morphologic stabilization of the dendritic arbor, and PKMζ downregulation was reported to underlie spatial familiarity.
In a second study, we examined the effect of environmental enrichment on PKMζprotein in the hippocampus and showed that PKMζprotein levels are downregulated across the different hippocampal zones and regions of female mice that were housed in an enriched environment (enriched female mice). Interestingly, we found no substantial PKMζdownregulation in enriched male mice, indicating that environmental enrichment affects PKMζin a sex-specific manner. Further, we found that environmental enrichment does not affect the performance of female mice on the hippocampus-dependent place-avoidance task, but did affect anxiety behavior. As this study only provides correlational data, we can only speculate about how environmental enrichment and subsequent changes in PKMζprotein levels affect animal plasticity and behavior. Based on previous studies of PKMζdownregulation, we speculate that enrichment-induced downregulation of PKMζprotein levels may enhance information processing by resetting the hippocampal synapses by means of depotentiation or longterm depression (LTD)-like mechanisms, and/or may underlie the reduced anxiety observed in enriched animals.
These studies yield fundamental new information regarding the role of PKMζin learning and memory. First, we found and quantified stable compartmentalization of PKMζin dendritic spines. Second, we found a potential role for PKMζin enriched environment-induced plasticity.
Citation
van de Nes, P. (2012). Long-term stabilization of PKMζ in dendritic spines in vitro and differential PKMζ protein regulation in environmental enrichment in vivo. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/16050
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Doctoral Dissertation