Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode
Description
Learning, memory and cognition are thought to require synaptic plasticity, specifically including as hippocampal long-term potentiation and depression (LTP and LTD). LTP versus LTD is induced by high- versus low-frequency stimulation (HFS versus LFS) but, stimulating β-adrenergic receptors (βARs) enables LTP induction also by LFS (1 Hz) or theta frequencies (~5 Hz) that don’t cause plasticity by themselves. In contrast to HFS-LTP, such βAR-LTP requires Ca2+-flux through L-type voltage-gated Ca2+-channels, not NMDA-type glutamate receptors (NMDARs). Surprisingly, we found that βAR-LTP still required a non-ionotropic scaffolding function of the NMDAR: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to its GluN2B subunit that mediates CaMKII movement to excitatory synapses. In hippocampal neurons, β-adrenergic stimulation with isoproterenol transformed LTD-type CaMKII movement to LTP-type movement, resulting in CaMKII movement to excitatory instead of inhibitory synapses. Additionally, isoproterenol enabled induction of a major cell-biological feature of LTP in response to LTD stimuli: increased SEP-GluA1 surface expression. Like for βAR-LTP in hippocampal slices, the isoproterenol effects on CaMKII movement and SEP-GluA1 surface expression involved L-type Ca2+-channels and specifically required β2-ARs. Taken together, these results indicate that isoproterenol transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode.
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National Institutes of Health
T32 GM007635
National Institutes of Health
P30 NS048154
National Institutes of Health
F32 AG066536
National Institutes of Health
R01 NS123050
National Institutes of Health
R01 AG055357
National Institutes of Health
R01 NS081248
National Institutes of Health
R01 AG067713