Depotentiation depends on IP₃ receptor activation sustained by synaptic inputs after LTP induction

Schematic depiction of the mechanism of LFS-induced depotentiation in hippocampal CA1 neurons. (A) Synaptic inputs after HFS or LFS activate NMDARs and mGluRs on postsynaptic CA1 pyramidal neurons. The activation of IP₃Rs on the membrane of the ER occurs downstream from group I mGluRs and phospholipase C in the signaling cascade. The increase in [Ca²⁺]_i due to the coactivation of NMDARs and IP₃Rs induces an increase in the free cytoplasmic levels of Ca²⁺/calmodulin complexes and IRBIT in the postsynaptic dendritic spines of CA1 neurons. (B) CaMKII autophosphorylated during and after priming HFS may continue to phosphorylate AMPA-type glutamate receptors on the dendritic spines of CA1 neurons to potentiate synaptic responses (to induce LTP), while IRBIT that is released from IP₃Rs into the cytoplasm and is phosphorylated may block the binding of Ca²⁺/calmodulin complexes to the regulatory domain of CaMKII and inhibit further CaMKII activation in postsynaptic CA1 neurons. CaMKII is active when Ca²⁺/calmodulin complexes are bound to its regulatory domain. (C) During synaptic transmission after LFS, the levels of free Ca²⁺/calmodulin complexes, which are not sequestrated by CaMKII in the presence of IRBIT, are increased to a point at which calcineurin is activated in the dendritic spines to dephosphorylate CaMKII and AMPARs at CA1 synapses, leading to a reduction in synaptic potentiation (depotentiation) in CA1 neurons.