Opposite regulation of inhibitory synaptic plasticity by α and β subunits of Ca2+/calmodulin-dependent protein kinase II

Induction of several forms of synaptic plasticity, a cellular basis for learning and memory, depends on the activation of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII acts as a holoenzyme consisting of alpha and beta subunits (alpha- and beta CaMKII). However, it remains elusive how the subunit composition of a CaMKII holoenzyme affects its activation and hence synaptic plasticity. We addressed this issue by focusing on long-term potentiation (LTP) at inhibitory synapses on cerebellar Purkinje neurons (PNs) (called rebound potentiation, RP). The contribution of each subunit to RP was examined by selective knock-down or overexpression of that subunit. Electrophysiological recording from a rat cultured PN demonstrated that beta CaMKII is essential for RP induction, whereas alpha CaMKII suppresses it. Thus, RP was negatively regulated due to the greater relative abundance of alpha CaMKII compared to beta CaMKII, suggesting a critical role of CaMKII subunit composition in RP. The higher affinity of beta CaMKII to Ca2+/CaM compared with alpha CaMKII was responsible for the predominant role in RP induction. Live-cell imaging of CaMKII activity based on the Forster resonance energy transfer (FRET) technique revealed that beta CaMKII enrichment enhances the total CaMKII activation upon a transient conditioning depolarization. Taken together, these findings clarified that alpha- and beta CaMKII oppositely regulate CaMKII activation, controlling the induction of inhibitory synaptic plasticity in a PN, which might contribute to the adaptive information processing of the cerebellar cortex.