Chapter 2 PKMζ, LTP maintenance, and the dynamic molecular biology of memory storage
Section snippets
The discovery of PKMζ
The notion that enzymes might maintain long-term memory was articulated by Crick (1984). Protein kinases have well-established roles in the transient enhancement of synaptic transmission thought to mediate short-term memory (Kandel and Schwartz, 1982). Therefore, one simple mechanism for long-term memory storage is the formation of a persistently active form of a kinase that could then sustain this enhancement over time. This notion was actively explored in the 1980s by the late Dr. James
PKMζ is synthesized from a PKMζ mRNA
Curiously, however, while an increase in PKMζ was seen during LTP maintenance, a decrease in PKCζ was not, i.e., there was no precursor–product relationship, as might be expected if PKMζ were produced by proteolytic cleavage. At that time, we reasoned that there might be new synthesis of PKCζ that could have replaced that cleaved to PKMζ. Therefore, to reveal the putative precursor–product relationship, we added protein synthesis inhibitors during the LTP experiments. To our surprise, however,
PKMζ synthesis is regulated by other protein kinases in LTP induction
As mentioned in the introduction, many molecules are critical for inducing LTP, in particular the protein kinases CaMKII, mitogen-activated protein kinase (MAPK), and PKA (Roberson et al., 1996; Sweatt, 1999). Other kinases important for translational regulation, the lipid kinase, phosphatidyl 3-kinase (PI3-kinase) (Kelly and Lynch, 2000; Sanna et al., 2002; Opazo et al., 2003), and the mammalian target of rapamycin (mTOR) (Tang et al., 2002; Cammalleri et al., 2003; Cracco et al., 2005) are
PKMζ potentiates postsynaptic AMPA receptor responses
The persistent increase in PKMζ correlates with the extent and duration of synaptic potentiation during LTP, but does the persistent kinase action of PKMζ cause synaptic potentiation? To address this question, we recombinantly expressed and purified PKMζ from the baculovirus/Sf9-overexpression system (in which endogenous PDK1 of the Sf9 insect cells phosphorylates the activation loop of the overexpressed PKMζ) (Ling et al., 2002). We then patched CA1 pyramidal cells in hippocampal slices with
PKMζ maintains late-LTP
If PKMζ is sufficient for synaptic potentiation, is it also necessary for the potentiation that maintains LTP? As mentioned in the introduction, although many inhibitors block LTP induction when applied around the time of tetanization, none had reversed established late-phase LTP prior to our work on PKMζ (Ling et al., 2002). In our initial investigation, we examined LTP maintenance 1 h after tetanization by comparing the effects of applications of two PKMζ inhibitors, chelerythrine, an
PKMζ maintains potentiation after synaptic tagging
PKMζ is synthesized by strong, but not weak afferent stimulation of synapses (Osten et al., 1996; Hernandez et al., 2003), and maintains late, but not early LTP. How does newly synthesized PKMζ affect only specific, activated synapses? One possibility is that the kinase might be involved in the process of synaptic tagging and capture (Sossin, 1996; Frey and Morris, 1997; Sajikumar et al., 2005). Synaptic tagging is the hypothesis, proposed by Sossin and by Frey and Morris, to explain how newly
PKMζ maintains long-term spatial memory storage in the hippocampus
The first evidence that PKMζ plays a role in memory came from work by Jerry Yin, Eric Drier, and colleagues (University of Wisconsin, Madison, WI) on odor avoidance conditioning in Drosophila (Drier et al., 2002). They found that overexpression of PKMζ during a narrow time-window after learning enhanced the persistence of memory. Conversely, blocking atypical PKC activity with a dominant negative or chelerythrine prevented persistent memory formation, without affecting short-term memory
PKMζ maintains long-term associative memory storage in the neocortex
Although the hippocampus stores spatial memories and the amygdala fear memories, the repository for most memories in the mammalian brain is thought to be neocortex. To test the role of PKMζ in storage in neocortex, Reut Shema and Yadin Dudai (Weizmann Institute, Rehovot, Israel) examined conditioned taste aversion (CTA), which is stored in the taste cortex located in the insular cortex (Shema et al., 2007). Rats were first presented with a novel taste, the conditioned stimulus (CS, such as
Conclusions
These studies show that PKMζ is the first known component of the storage mechanism for long-term associative memory. The unique structure and function of the PKMζ gene, mRNA, and protein provide a relatively simple, essential molecular mechanism for information storage through synthesis of a constitutively active protein kinase (Sacktor et al., 1993; Hernandez et al., 2003), which persistently maintains enhanced synaptic transmission at synapses. Although this mechanism is quite different from
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