Our present result that week old PKA mice

Our present result that ≤2-week-old 150ΔPKA mice express normal LTP that does not depend on CP-AMPARs also supports the collective findings of previous work showing that LTP mechanisms are remarkably adaptable in juvenile animals compared with adults. In particular, GluA1 knockout, S845A/S831A, and AKAP150 D36 mice all exhibit impaired LTP as adults but express normal LTP as juveniles (Jensen et al., 2003, Lee et al., 2003, Lu et al., 2007, Zamanillo et al., 1999). Accordingly, elegant work by Granger et al. (2013) demonstrated that either GluA1 or GluA2 alone (or even a kainate receptor) can support LTP at CA1 synapses in ∼2- to 3-week-old animals, providing that a sufficient extrasynaptic reserve pool of receptors exists. Thus, as proposed by Granger et al. (2013), LTP in juveniles may be more dependent on and driven by PSD structural remodeling to create more slots for AMPARs, but these slots then have the potential to be filled by a variety of different receptor types through the anchoring functions of auxiliary subunits, such as transmembrane AMPA receptor regulatory proteins, and through regulation by a variety of overlapping signaling mechanisms (Tomita et al., 2005). Yet by adulthood, the extrasynaptic AMPAR reserve pool and LTP become much more dependent on GluA1, and in parallel, the importance of AKAP-PKA signaling, GluA1 phosphorylation, and CP-AMPARs in regulating LTP increase. Overall, adaptability in LTP and its underlying mechanisms appears to be a characteristic of the juvenile hippocampus that decreases by adulthood. However, as shown here, some of the same Magnolol australia and mechanisms that are non-essential for LTP in juveniles can at the same time still be crucial for LTD. Although the prominence of NMDAR-dependent LTD decreases during postnatal development to adulthood, NMDAR-LTD mechanisms, including GluA1 S845 regulation, appear to remain more constant during development (Babiec et al., 2014, Dudek and Bear, 1993, He et al., 2009, Lee et al., 2003, Lee et al., 2010). Importantly, He et al. (2009) demonstrated that LTD removes peri-synaptic CP-AMPARs in an S845-dependent manner in 3- to 4-week-old mice. However, it remains to be determined whether CP-AMPAR contributions to LTD remain constant on through to adulthood. In addition to having oversized contributions to synaptic strength due to high single-channel conductance, synaptic CP-AMPARs can also confer other unique properties resulting in plasticity of plasticity itself, so-called meta-plasticity. Meta-plastic changes conferred by CP-AMPARs include enhanced LTP at hippocampal synapses (Megill et al., 2015, Sanderson et al., 2012) and the ability to express a unique mGluR1-mediated mechanism that removes CP-AMPARs from synapses in the amygdala, nucleus accumbens, ventral tegmentum, and cerebellum (Bellone et al., 2011, Clem and Huganir, 2013, Kelly et al., 2009, Loweth et al., 2013). Here we show that CP-AMPAR recruitment to synapses can also positively regulate NMDAR-dependent LTD, but only if CP-AMPARs remain in the synapse transiently, such that the change in meta-plasticity is brief. If the precise balance of PKA/CaN signaling shifts in either direction, then meta-plasticity is disrupted and LTD is impaired either due to insufficient CP-AMPAR recruitment or removal. Importantly, only through co-anchoring of PKA and CaN to AKAP150 can such precisely balanced bi-directional control be achieved to produce a transient burst in CP-AMPAR Ca2+ signaling that augments NMDAR signaling in LTD.
Experimental Procedures
Author Contributions
Acknowledgments