Mossy fibre synaptic NMDA receptors trigger non-Hebbian long-term potentiation at entorhino-CA3 synapses in the rat

Hippocampal CA3 pyramidal cells receive two independent afferents from the enthorinal cortex, i.e. a direct input via the temporoammonic pathway (TA, perforant path) and an indirect input via the mossy fibres (MF) of dentate granule cells. In spite of past suggestions that the TA is assigned an important role in exciting the pyramidal cells, little is known about their physiological properties. By surgically making an incision through the sulcus hippocampi and a small part of the dentate molecular layer, we succeeded in isolating TA-mediated monosynaptic responses in CA3 stratum lacunosum-moleculare. The TA-CA3 synaptic transmission was completely blocked by a combination of D,L-2-amino-5-phosphonopentanoic acid (AP5) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), NMDA and non-NMDA receptor antagonists, respectively, and displayed paired-pulse facilitation and NMDA receptor-dependent long-term potentiation, which are all typical of glutamatergic synapses. We next addressed the heterosynaptic interaction between TA-CA3 and MF-CA3 synapses. The TA-CA3 transmission was partially attenuated by single-pulse MF pre-stimulation at inter-pulse intervals of up to 70 ms. However, surprisingly, burst stimulation of the MF alone induced long-lasting facilitation of TA-CA3 synaptic efficacy. This non-Hebbian form of synaptic plasticity was efficiently prevented by local application of AP5 into the MF synapse-rich area. Therefore, MF-activated NMDA receptors are responsible for the heterosynaptic modification of TA-CA3 transmission, and thereby, the history of MF activity may be etched into TA-CA3 synaptic strength. Our findings predict a novel form of spatiotemporal information processing in the hippocampus, i.e. a use-dependent intersynaptic memory transfer.