CaMKII binding to GluN2B flips a β-adrenergic switch from synaptic depression to potentiation

Abstract

AbstractLearning, memory and cognition are thought to require forms of synaptic plasticity such as hippocampal long-term potentiation and depression (LTP and LTD), and such plasticity can be modulated by β-adrenergic stimulation with isoproterenol or norepinephrine. For instance, 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. In contrast to HFS-LTP, such βAR-LTP requires signaling by L-type voltage-gated Ca2+-channels, not NMDA-type glutamate receptors (NMDARs). Surprisingly, we found that βAR-LTP still required a non-ionotropic NMDAR function: the stimulus-induced binding of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) 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 the βAR-LTP in hippocampal slices, the effects of isoproterenol on CaMKII movement and SEP-GluA1 surface expression involved L-type Ca2+-channels. Taken together, these results indicate that isoproterenol transforms LTD stimuli to LTP signals by switching CaMKII movement and GluN2B binding to LTP mode.One Sentence SummaryBuonarati et al. show that β-adrenergic stimulation enables LTP induction in response to LTD stimuli by switching synaptic CaMKII movement to LTP mode.