Long-term potentiation of the perforant path in vivo is associated with increased glutamate release

Long-term potentiation (LTP) of synaptic transmission following brief trains of high-frequency stimulation in hippocampal pathways has attracted attention as a possible physiological correlate of memory. The mechanism of LTP is little understood, and what evidence there is suggests that both pre- and postsynaptic mechanisms are involved1-7. Previous findings that Ca2+ is required for LTP8,9, and that LTP is accompanied by a prolonged increased in Ca2+ uptake10, suggest that an increase in impulse-dependent release of transmitter, a process critically dependent on presynaptic Ca2+ levels11,12, may be an important component of this form of synaptic plasticity. A recent report13 that release of previously accumulated 3H-D-aspartate is increased following tetanic stimulation of afferent fibres to CA1 pyramidal cells in hippocampal slices is also consistent with a presynaptic mechanism. However, there has been no direct evidence relating LTP to an increased stimulus-dependent release of transmitter. We have now investigated whether LTP in the perf orant path (PP) of the rat is associated with a change in the release of neurotransmitter. A modification of the push-pull cannula technique has enabled us to infuse 3H-glutamine and measure the subsequent release of newly synthesized 3H-glutamate, and at the same time to monitor the field potentials evoked in the dentate gyrus by stimulation of the PP. We have found a prolonged increase in the release of glutamate, the probable transmitter of the PP14,15, following the induction of LTP in this pathway.