Role of postsynaptic inositol 1, 4, 5-trisphosphate receptors in depotentiation in guinea pig hippocampal CA1 neurons

• Activation of IP3 receptors during the priming HFS triggers the mechanism responsible for depotentiation at CA1 synapses.
• IP3 receptors activated during the priming HFS decrease free Ca2+/calmodulin complex in postsynaptic CA1 neurons.
• The decrease of free Ca2+/calmodulin complex facilitates activation of IP3 receptors during/after the LFS in these neurons.
• Activation of IP3 receptors facilitated during/after the LFS reduces LTP amplitude and induces depotentiation at CA1 synapses.

The long-term potentiation (LTP) in the field excitatory postsynaptic potential (EPSP) induced at hippocampal CA1 pyramidal neuron synapses by delivery of high frequency stimulation (HFS), a tetanus of 100 pulses at 100 Hz, is decreased (depotentiation) by a train of low frequency stimulation (LFS) of 1000 pulses at 2 Hz applied 30 min later. Inositol 1, 4, 5-trisphosphate receptors (IP3Rs) activated both during the HFS and after the LFS are involved in this depotentiation, the former triggering, and the latter modifying, LTP induction (decreasing the amplitude of the LTP established by the priming HFS). Furthermore, the decrease in the LTP at CA1 synapses requires activation of IP3Rs during LFS and activation of calcineurin after LFS. These results suggest that, at hippocampal CA1 neuron synapses, HFS-induced IP3R activation, which is modulated by the subsequent LFS, results in postsynaptic protein dephosphorylation after the LFS, leading to a decrease in the field EPSP and in the HFS-induced LTP.