| The entorhinal cortex relays sensory information both directly and indirectly to hippocampal CA1 neurons through the perforant path (PP) and Schaffer collateral synapses (SC), respectively. Although the indirect SC pathway has received the vast majority of attention to date, recent behavioral and physiological studies indicate an important and unique role for the direct PP input in hippocampal functions involved in learning and memory. Despite such recent progress, however, the functional properties of presynaptic terminals of the perforant pathway, which are critical in determining the fidelity, strength, and dynamic adaptations of synaptic communication and which will contribute to the differential processing of information through the direct versus indirect pathways, are presently unknown. Moreover, the mechanisms of expression of long-term potentiation (LTP), widely considered to be a cellular basis for learning and memory, have not yet been characterized at perforant path synapses, even though the importance of LTP in this pathway is underscored by its correlation with enhanced spatial learning in mice.;Therefore, using a combination of two-photon FM 1-43 imaging of vesicle cycling and electrophysiological recordings in hippocampal slices, I have directly assayed presynaptic function and long-term plasticity at individual PP terminals and report four significant and novel results. First, I find that PP inputs have a lower efficacy of release compared to SC inputs to the same CA1 neurons. Second, I show that this low release efficacy is due to a smaller contribution of presynaptic N-type voltage-gated Ca2+ channels to the release process at PP synapses. Third, I show that at least two forms of PP LTP, both dependent on NMDARs and L-type voltage-gated Ca 2+ channels, enhance this low efficacy of release as a cellular mechanism of plasticity expression. The NMDAR and L-type channel dependence of this presynaptic enhancement during PP LTP resembles that previously described for SC synapses. Fourth, and perhaps most interestingly, I find that the enhanced release efficacy contributing to PP LTP expression is largely due to a recruitment of presynaptic N-type Ca2+ channels to the release process.;Together these results highlight the dual role of the N-type channel as a molecular substrate underlying PP presynaptic function and LTP, thus representing a novel presynaptic mechanism for fine-tuning release properties of distinct classes of synapses on a common postsynaptic neuron and for regulating synaptic function during long-term synaptic plasticity. In addition, and consistent with a "unified model" of LTP, these results further provide support for the existence of a general presynaptic module of LTP expression that is triggered by NMDAR and L-type Ca2+ channel activation. Finally, given the opposite roles of the N-type Ca2+ channel in basal presynaptic function and LTP expression of PP inputs, my results present this presynaptic channel as a specific molecular target for future studies investigating the particular role of PP LTP in hippocampal-dependent learning and memory. |
