Stimulating β-adrenergic receptors promotes synaptic potentiation by switching CaMKII movement from LTD to LTP mode

Abstract

Learning, memory and cognition are thought to require synaptic plasticity, specifically including 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 surface expression of GluA1 fused with super-ecliptic pHluorein (SEP-GluA1). 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.