CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca 2+ Signals during LTP Induction, but Not Maintenance

Abstract

SUMMARY CaMKII plays a critical role in decoding calcium (Ca2+) signals to initiate long-lasting synaptic plasticity. However, the properties of CaMKII that mediate Ca2+ signals in spines remain elusive. Here, we measured CaMKII activity in spines using fast-framing two-photon fluorescence lifetime imaging. Following each pulse during repetitive Ca2+ elevations, CaMKII activity increased in a stepwise manner. Thr286 phosphorylation slows the decay of CaMKII and thus, lowers the frequency required to induce spine plasticity by several fold. In the absence of Thr286 phosphorylation, increasing the stimulation frequency results in high peak mutant CaMKIIT286A activity that is sufficient for inducing plasticity. Our findings demonstrate that Thr286 phosphorylation plays an important role in induction of LTP by integrating Ca2+ signals, and it greatly promotes, but is dispensable for the activation of CaMKII and LTP.

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

“…Modest relearning occurred over the three subsequent trials (trials 14-16 in Fig.4C), perhaps due to non-transfected cells (see Methods for quantification and (Moser and Moser, 1998; Rumpel et al, 2005) for evidence that behavioral effects do not require that all neurons are affected). According to the model of (Chang et al, 2017), CaMKII has no role in memory maintenance; because some other process encodes memory, that information should be retrievable despite the action of CaMKII*. The results in Fig.…”

“…Other work using the same mutation (Villers et al, 2014) measured LTP over longer periods and found that normal LTP was not maintained but, rather, was replaced by a form of potentiation that does not have synapse specificity or NMDAR dependence. In summary, the model of (Chang et al, 2017; Murakoshi et al, 2017) leaves a large number of experimental results demonstrating long-lasting changes in CaMKII unexplained (Ahmed and Frey, 2005; Fukunaga et al, 1993; Lengyel et al, 2004; Otmakhov et al, 2004) and is inconsistent with results showing that manipulations of CaMKII during the maintenance period can affect LTP (Barcomb et al, 2016; Sanhueza et al, 2011) and behavior (Figs. 3,4).…”

“…Finally, (Chang et al, 2017; Murakoshi et al, 2017), in support of their model, refer to the persistence of LTP maintenance in the T286A CaMKII-alpha mutant, a mutant that prevents persistent activation of CaMKII. However, they only follow maintenance for short periods.…”

“…A recent model posits that the only role of CaMKII is during the minute period during and after LTP induction (Chang et al, 2017). During this period, autophosphorylation of CaMKII integrates the Ca 2+ signal (Lee et al, 2009) (but see (Otmakhov et al, 2015)).…”

PAM forms an atypical SCF ubiquitin ligase complex that ubiquitinates and degrades NMNAT2

“…Fluorescence lifetime images were collected by 128 x 128 pixels acquired at 2 ms/line and averaged over 24 frames. The fluorescence lifetime of mEGFP was measured by curve fitting as previously described (65). Unpaired Student's t-tests (two-tailed, 95% confidence) compared RPM-1::mEGFP alone with RPM-1::mEGFP + mCherry::FSN-1, or with RPM-1::mEGFP + mCherry expressed in the mechanosensory neurons.…”