Local protein synthesis and GABA_B receptors regulate the reversibility of long-term potentiation at murine hippocampal mossy fibre-CA3 synapses

Reversal of long-term potentiation (LTP) by long trains of low-frequency stimulation is generally referred to as depotentiation. One of the intriguing aspects of depotentiation is that the magnitude of depotentiation is inversely proportional to the time lag of depotentiation stimulation following LTP induction. Although the mechanisms underlying depotentiation have been widely explored, the factors that regulate the susceptibility of LTP to depotentiation stimulation remain largely unclear. We now report that multiple trains of high-frequency stimulation provide immediate synaptic resistance to depotentiation stimulation at the mossy fibre-CA3 synapses. The synaptic resistance to depotentiation stimulation depends on the amount of synaptic stimulation used to induce LTP; it is prevented by protein synthesis inhibitors and is input specific. In contrast, neither the transection of mossy fibre axons near granule cell somata nor the application of RNA synthesis inhibitors influences synaptic resistance to depotentiation stimulation. We also provide evidence that the induction of depotentiation is regulated by GABA_B receptors. Application of a GABA_B receptor antagonist significantly promoted the synaptic resistance to depotentiation stimulation, whereas inhibition of GABA transport delayed the onset of this synaptic resistance. These results suggest that local protein synthesis is required for the development of synaptic resistance to depotentiation stimulation, whereas the activation of GABA_B receptors promotes the susceptibility to depotentiation stimulation. These two factors may crucially regulate the reversal and stability of long-term information storage.