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Experimental induction of trans-synaptic long-term potentiation

Since the early 70’s of the past century, long-term potentiation (LTP) evoked experimentally by high-frequency stimulation (HFS) protocols is a popular technique for the study of cellular and molecular mechanisms underlying learning-dependent changes in synaptic strength. It was described for the first time in the hippocampus of anesthetized rabbits, but these seminal studies were followed by detailed analyses of molecular events involved in the generation of LTP mostly carried out in hippocampal slices.

The developing of experimental techniques to evoke LTP in behaving mice and rats have opened additional experimental possibilities and new theoretical questions. In particular, there is no consolidated evidence whether the experimental induction of LTP is restricted to neurons contacted monosynaptically from the stimulating afferent pathway or whether HFS presentations are also affecting contiguous (bi- or poli-) synapses. This interesting question (also extensible to the synaptic changes taking place during actual learning situations) has prompted us to the development of an experimental model in mice by which it will be possible to study LTP evoked in neurons not directly (i.e., monosynaptically) contacted by the stimulated afferent pathway. In an initial set of experiments, we have studied in behaving mice the electrophysiological responses of five synapses (PPi-CA3i; PP-CA1i; PP-CA1c; CA3-CA1i and CA3-CA1c), following a HFS protocol presented to the performant pathway (PPi). Preliminary results suggest the presence of trans-synaptic LTP in the hippocampus. Presently we are preparing a second set of experiments to determine the specificity of molecular events taking place in those trans-synaptic neurons and their similitudes and differences with those evoked monosynaptically. In collaboration, with Barco’s lab we will use Fos immunostaining and novel activity reporter mouse strains to monitor the activation of neurons in the ipsi- and contralateral hippocampi after LTP induction.

Trans-synaptic induction of long-term potentiation. A, A diagram of the experimental design. Wild-type mice were implanted with stimulating electrodes in the perforant pathway (PP) and recording electrodes in the ipsilateral CA3 and CA1 and in the contralateral CA1. B, Averaged field potentials evoked before (continuous lines) and after (dotted lines) high-frequency stimulation (HFS) of the PP. C, LTP was evoked at the three recording sites. LTP induction at the CA1i and CA1c recording sites was further confirmed by direct stimulation of the CA3 area (not illustrated).

Trans-synaptic induction of long-term potentiation. A, A diagram of the experimental design. Wild-type mice were implanted with stimulating electrodes in the perforant pathway (PP) and recording electrodes in the ipsilateral CA3 and CA1 and in the contralateral CA1. B, Averaged field potentials evoked before (continuous lines) and after (dotted lines) high-frequency stimulation (HFS) of the PP. C, LTP was evoked at the three recording sites. LTP induction at the CA1i and CA1c recording sites was further confirmed by direct stimulation of the CA3 area (not illustrated).