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    • A requirement for active PKA signaling

    2022-11-17

    A requirement for active PKA signaling during LTD induction was proposed in studies characterizing AKAP150 D36mice (Lu et al., 2008), but linking impaired LTD in D36 mice to PKA signaling deficits was complicated by subsequent work showing substantial increases in the number of dendritic spines and overall basal excitatory and inhibitory input to CA1 neurons in juvenile D36 mice (Lu et al., 2011). Importantly, we observed only a very small increase in spine density and did not detect any significant changes in excitatory or inhibitory input to CA1 neurons in 150ΔPKA mice. The reasons for these differences in basal transmission measurements are unclear but could be due to the ΔPKA PF-670462 being more specific than the larger D36 truncation, as well as possibly differences in recording conditions. Nonetheless, the findings of impaired LTD in both 150ΔPKA and D36 mice are in agreement and indicate that changes in basal transmission in D36 mice had little impact on the impaired LTD phenotype. Our findings and model are also consistent with the idea that highly dynamic, localized cycles of phosphorylation and dephosphorylation confined to a small pool of GluA1 homomers can have major impacts on synaptic function (Guire et al., 2008). As mentioned above, localized, rapid phosphorylation cycling would be impossible to detect using biochemical methods, thus the absolute amounts and steady-state levels of bulk GluA1 phosphorylation are not likely to fully represent underlying signaling dynamics. Nonetheless, biochemical measurements showing S845 phosphorylation decreases in 150ΔPKA and increases in 150ΔPIX mice may still reflect that imbalances in local, postsynaptic PKA versus CaN signaling are also occurring in real time. It will be interesting to determine whether other kinases that phosphorylate GluA1, such as CaMKII which is required for both LTP and LTD (Coultrap et al., 2014), also regulate CP-AMPAR synaptic recruitment and/or removal in coordination with PKA and CaN during LTD. The model in Figure 7 depicts the CP-AMPARs participating in LTD induction as being physically recruited to synapse, but alternatively, these CP-AMPARs could be functionally recruited to participate in synaptic signaling from peri-synaptic locations due to glutamate spill over during prolonged LFS. Such an engagement of peri-synaptic CP-AMPARs could be consistent with work by He et al. (2009) showing that glutamate spillover can unmask an antagonist-sensitive pool of CP-AMPARs that is removed by LTD induction in WT mice and is not present in S845A mice. Our experiments continuously applying NASPM during LFS cannot distinguish between these two possibilities, because both the stimulus and the antagonist were presented together for a long period of time, such that there is no way to tell when and where use-dependent CP-AMPAR block occurs. However, the findings of more pronounced LTD inhibition, and even potentiation, when NASPM is washed out post-induction suggest that CP-AMPARs are physically recruited and then retained in the synapse if blocked by NASPM to prevent removal. In addition, our measurements of NASPM-sensitive AMPAR rectification during LTD induction, which we performed while pausing LFS delivery (thus making spillover unlikely), are also consistent with transient physical CP-AMPAR recruitment to the synapse. Accordingly, in 150ΔPIX mice, where CP-AMPARs are not removed after induction (as shown by antagonist sensitivity and rectification), LTD expression is obscured by the continuing presence of these higher conductance receptors. Although secondary to our main findings of CP-AMPAR engagement in LTD, we also made interesting new observations regarding the CP-AMPAR dependence of LTP that reinforce the idea that there is a remarkable amount of developmental plasticity in LTP mechanisms. Our findings of a transition in the CP-AMPAR antagonist sensitivity of LTP between P14 and P17 are in agreement with a previous study that found changes in the CP-AMPAR dependence of LTP induced by 1 × 100 Hz HFS during the third postnatal week (Lu et al., 2007). However, our results here indicate that this developmental switch away from LTP engagement of CP-AMPARs is more abrupt than previously appreciated and occurs over only ∼3 days. Although differences in LTP induction stimuli and recording conditions can also be relevant (Gray et al., 2007, Guire et al., 2008, Lu et al., 2007), such an abrupt developmental transition could explain how different studies that analyzed 2- to 3-week-old animals obtained opposite results regarding CP-AMPARs in LTP, depending on whether the age distribution was possibly skewed toward 2 or 3 weeks (Adesnik and Nicoll, 2007, Gray et al., 2007, Plant et al., 2006, Yang et al., 2010). Indeed, in our prior work showing that CP-AMPARs contribute to enhanced LTP in 150ΔPIX mice, we recorded from a mix of 2- to 3-week-old mice and found, using 1 × 100 Hz induction as here, that CA1 LTP in WT mice was not inhibited by IEM1460 (Sanderson et al., 2012).