Pre- vs. Post-Synaptic Forms of LTP in Two Branches of the Same Hippocampal Afferent

There has been considerable controversy about pre- vs. post-synaptic expression of memory related Long-Term Potentiation (LTP), with corresponding disputes about underlying mechanisms. We report here an instance in male mice, in which both types of potentiation are expressed but in separate branches of the same hippocampal afferent. Induction of LTP in the dentate gyrus (DG) branch of the lateral perforant path (LPP) reduces paired-pulse facilitation, is blocked by antagonism of cannabinoid receptor type-1, and is not affected by suppression of postsynaptic actin polymerization. These observations are consistent with presynaptic expression. The opposite pattern of results was obtained in the LPP branch that innervates the distal dendrites of CA3: LTP did not reduce paired-pulse facilitation, was unaffected by the cannabinoid receptor blocker, and required postsynaptic actin filament assembly. Differences in the two LPP termination sites were also noted for frequency facilitation of synaptic responses, an effect that was reproduced in a two-step simulation by small adjustments to vesicle release dynamics. These results indicate that different types of glutamatergic neurons impose different forms of filtering and synaptic plasticity on their afferents. They also suggest that inputs are routed to, and encoded by, different sites within hippocampus depending upon the pattern of activity arriving over the parent axon. Significance Statement Within hippocampus, Long Term Potentiation (LTP), a substrate for memory encoding, is expressed at pre- and post-synaptic sites in a sub-field specific manner. However, the question of whether the pre- or post-synaptic element determines the location of the potentiated state remains. We have addressed this by taking advantage of the anatomical organization of the lateral perforant path (LPP), which branches to innervate two distinct types of principal cells in dentate gyrus (DG) and field CA3. Results indicate that terminals from the same LPP axons use either pre- or post-synaptic LTP signifying that the target neuron specifies the nature of potentiation. Such target specification allows the hippocampus to route incoming information into two channels that have radically different processing modes.