Interaction between Long-Term Potentiation and Depression in CA1 Synapses: Temporal Constrains, Functional Compartmentalization and Protein Synthesis

Information arriving at a neuron via anatomically defined pathways undergoes spatial and temporal encoding. A proposed mechanism by which temporally and spatially segregated information is encoded at the cellular level is based on the interactive properties of synapses located within and across functional dendritic compartments. We examined cooperative and interfering interactions between long-term synaptic potentiation (LTP) and depression (LTD), two forms of synaptic plasticity thought to be key in the encoding of information in the brain. Two approaches were used in CA1 pyramidal neurons of the mouse hippocampus: (1) induction of LTP and LTD in two separate synaptic pathways within the same apical dendritic compartment and across the basal and apical dendritic compartments; (2) induction of LTP and LTD separated by various time intervals (0–90 min). Expression of LTP/LTD interactions was spatially and temporally regulated. While they were largely restricted within the same dendritic compartment (compartmentalized), the nature of the interaction (cooperation or interference) depended on the time interval between inductions. New protein synthesis was found to regulate the expression of the LTP/LTD interference. We speculate that mechanisms for compartmentalization and protein synthesis confer the spatial and temporal modulation by which neurons encode multiplex information in plastic synapses

Mécanismes physiopathologiques du déficit cognitif associé aux mutations du gène IL-1 receptor accesory protein like-1

Les mutations du gène IL1-Receptor Accessory Protein Like 1 (IL1RAPL1) sont associées à un déficit cognitif isolé ou associé à l autisme. Cette protéine transmembranaire appartient à une nouvelle famille de récepteurs à l IL-1. Sa structure est similaire à celles de ces récepteurs mais elle possède en plus un domaine cytoplasmique spécifique à son extrémité carboxy-terminale. IL1RAPL1 interagit via cette région avec NCS-1, senseur calcique neuronal impliqué dans la régulation de l exocytose. En utilisant une lignée de cellules neuroendocrines, nous avons montré que la surexpression d IL1RAPL1 a un effet inhibiteur sur l exocytose et sur les courants calciques de type N. Cette inhibition est dépendante de l'interaction d'IL1RAPL1 avec NCS-1. La région C-terminale d IL1RAPL1 contient également un motif d interaction avec PSD-95, molécule d échafaudage de la synapse excitatrice. La caractérisation du modèle murin montre le rôle d IL1RAPL1 dans la régulation de la localisation synaptique de PSD-95 en contrôlant la voie des kinases JNK et la phosphorylation de PSD-95. Le déficit en IL1RAPL1 aboutit in vivo à une diminution du nombre de synapses excitatrices dans l hippocampe et une altération de la plasticité synaptique. Dans le cervelet, l inactivation d IL1RAPL1 induit un déséquilibre de la balance inhibition/excitation au cours du développement post-natal. L ensemble de ces résultats montre qu IL1RAPL1 est impliquée dans le fonctionnement de la synapse et la maturation des réseaux neuronaux. De plus, la régulation de la voie de signalisation JNK par IL1RAPL1 ouvre des perspectives de correction du déficit synaptique présent chez la souris et peut-être, chez l homme.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Intracompartmental interaction between strong forms of LTP and LTD in the apical dendritic compartment.

<p>The values represent the relative change in fEPSP amplitude with respect to the baseline (100%).</p><p>*Statistically significant from control at p<0.05.</p

Transcompartmental interaction between strong forms of LTP and LTD (LTP and LTD are induced at basal and apical dendrites, respectively).

<p>The values represent the relative change in fEPSP amplitude with respect to the baseline (100%).</p><p>*Statistically significant from control at p<0.05.</p

Interactions between LTP and LTD within the same apical (INTRA) and across dendritic (TRANS) compartments.

<p><b>TI</b>: Time interval. <b>FP</b>: Form of synaptic plasticity. <i>No Interaction</i> indicates that we observed neither cooperation nor interference between LTP and LTD. nd: not determined. The index is the observed change in synaptic plasticity as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029865#pone-0029865-g007" target="_blank">Fig. 7A</a>.</p

Temporal restriction and dendritic compartment specificity for the cooperative interaction between LTP and LTD.

<p>(<b>A</b>): Failure to induce a cooperative interaction (the conversion of weak LTD into strong LTD) between strong LTP induced in apical pathway S2 (bottom blue trace) and weak LTD induced in apical pathway S1 (top blue trace) with a 45 min time interval between inductions. However with a 90 min time interval between inductions (red traces), cooperative interaction is observed. (<b>B</b>): Absence of cooperative interaction between strong LTP and weak LTD across dendritic compartments. Weak LTD induced in the S1 basal pathway (top panel) is not transformed into strong LTD after induction of strong LTP in the apical pathway S1 (bottom panel) with either, a 45 min (blue traces) or a 90 min (red traces) time interval between inductions. (<b>C</b>): Graphs representing the LTP change (top) and LTD change (bottom) indexes for the intracompartmental interaction between a strong form of LTP and a weak form of LTD. An absence of a cooperative effect is evidenced by LTP and LTD change indexes close to 1. In contrast, an LTD change index higher than 1 demonstrated a cooperative effect between LTP and LTD with a time interval of 90 min. The LTP change index remained close to 1. (<b>D</b>): Graphs representing the LTP change (top) and LTD change (bottom) indexes for the transcompartmental interaction between a strong form of LTP and a weak form of LTD. No deviation from 1 is observed for the LTP or LTD change index at 45 or 90 min time interval; demonstrating the absence of cooperative interaction between LTP and LTD across dendritic compartments. In all the figures each independent data set was obtained from 6 mice. S1 and S2 represent two independent afferents synapsing on the apical (A) or on the basal and the apical dendritic compartment, respectively (B).</p

Dependency on protein synthesis and transcription of the interference between LTP and LTD.

<p>Within the same dendritic compartment: (<b>A</b>): Disruption of the expression of strong LTP (apical pathway S2, bottom gray trace) by the protein synthesis blocker anisomycin (20 µM, horizontal bar) prevents the interference over the subsequent expression of strong LTD (apical pathway S1, top gray trace). Time interval between inductions is 45 min. To facilitate visualization of the rescue of the interference, the expression of the interaction between strong LTP and strong LTD in normal <i>r</i>ACSF (without blockers) is shown in light blue traces in all panels. (<b>B</b>): Disruption of the expression of strong LTP (apical pathway S2, bottom hollow trace) by the transcription blocker actinomycin (40 µM, horizontal bar) did not prevent the interference over the subsequent expression of strong LTD (apical pathway S1, top hollow trace). Time interval between inductions is 45 min. <i>Across dendritic compartments</i>. (<b>C</b>): Disruption of the expression of strong LTP (apical pathway S2, bottom gray trace) by anisomycin (horizontal bar) did not significantly prevent the interference over the subsequent expression of strong LTD (basal pathway S1, top gray trace). Time interval between inductions is 15 min. (<b>D</b>): Disruption of the expression of strong LTP (apical pathway S2, bottom hollow trace) by actinomycin (horizontal bar) did not significantly prevent the interference over the subsequent expression of strong LTD (basal pathway S1, top hollow trace). Time interval between inductions is 15 min. In all the figures each independent data set was obtained from 6 mice. S1 and S2 represent two independent afferents synapsing on the apical (A, C) or on the basal and the apical dendritic compartment, respectively (B, D).</p

Transcompartmental interaction between strong forms of LTP and LTD (LTP and LTD are induced at apical and basal dendrites, respectively).

<p>The values represent the relative change in fEPSP amplitude with respect to the baseline (100%).</p><p>*Statistically significant from control at p<0.05.</p

Mild interference between strong forms of LTP and LTD across dendritic compartments.

<p>(<b>A</b>): Absence of interference between strong LTD induced in the basal dendritic compartment (pathway S1, top blue trace) and strong LTP induced in the apical dendritic compartment (pathway S2, bottom blue trace). Time interval between inductions is 45 min. To facilitate visualization of interference, the expression of control (unpaired) strong LTD (top) and strong LTP (bottom) is shown in all panels (grey traces). (<b>B</b>): Similarly, strong LTP induced in the apical pathway S2 (bottom blue trace) does not interfere with the subsequent expression of strong LTD induced in the basal pathway S1 (top blue trace). Time interval between inductions is 45 min. (<b>C</b>): A mild interference of strong LTD (basal pathway S1, top blue trace) over the expression of strong LTP (apical pathway S2, bottom blue trace) is observed with a 15 min time interval between inductions. (<b>D</b>): A modest interference is also observed for strong LTP (apical pathway S2, bottom blue trace) over the expression of strong LTD (basal pathway S1, top blue trace) with a 15 min time interval. (<b>E</b>): In spite of the observed mild transcompartmental interference, simultaneous induction of strong LTD (basal pathway S1, top blue trace) and strong LTP (apical pathway S1, bottom blue trace) results in blockage of the expression of strong LTD. (<b>F</b>): Graphs representing LTP change (top) and LTD change (bottom) indexes (see text for details). Negative time intervals correspond to the change in the first induced form of synaptic plasticity, positive time intervals correspond to the change in the second (subsequent) form of synaptic plasticity. Similar to the intracompartmental studies, when first induced, LTP and LTD change indexes show values close to 1 (no interference). LTP and LTD change indexes are smaller than 1 (interference) for the second induced form of plasticity only at 15 min. time interval, as no interaction was observed at 45 min. time interval (LTP and LTD change index∼1). At time interval 0 min, LTD change is smaller than 1, while LTP change is about 1. Each independent data set was obtained from 6 mice. S1 and S2 represent independent afferents synapsing on the basal and the apical dendritic compartments. Representative traces are shown (gray: control; dark gray: interaction; 1: baseline and 2: after synaptic plasticity induction). Scale bar is 2 mV and 5 msec. Enlarged traces are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029865#pone.0029865.s002" target="_blank">Fig. S2</a>.</p

Expression of strong and weak forms of LTP and LTD in the basal and apical dendritic compartments of CA1 pyramidal neurons.

<p>(<b>A, B</b>): A strong form of LTD that expressed the protein synthesis dependent late phase of LTD (L-LTD) was induced by paired pulses of low frequency stimulation (PP-1Hz: 50 msec interpulse interval at 1 Hz for 15 min) in the basal (<b>A, dark gray circles</b>, n = 6) and apical (<b>B, dark gray circles</b>, n = 6) dendritic compartments. Conversely, a weak form of LTD that expressed the protein synthesis independent early phase of LTD (E-LTD) was induced after a single train of low frequency stimulation (1 Hz: 1 train of 15 min at 1 Hz) in the basal (<b>A, light gray circles</b>, n = 5) and apical (<b>A, light gray circles</b>, n = 5) dendritic compartments. Blockage of new protein synthesis transformed strong LTD into weak LTD in the basal (<b>A, open circles</b>, n = 6) and apical (<b>B, open circles</b>, n = 6) dendritic compartments (anisomycin, an inhibitor of translation, was added between −20 min and +20 min of recording). (<b>C, D</b>): A strong form of LTP that expressed the late phase of LTP (L-LTP) was induced by 4 trains of high frequency stimulation (HFS, 4 trains of 1-sec at 100 Hz stimulation, 5 min inter-train interval) in the basal (<b>C, dark gray circles</b>, n = 6) and apical (<b>D, dark gray circles</b>, n = 6) dendritic compartments. Like with strong LTD, blockage of new protein synthesis transformed strong LTP into weak LTP that expressed the early phase of LTP in the basal (<b>C, open circles</b>, n = 6) and apical (<b>D, open circles</b>, n = 6) dendritic compartments (anisomycin was added between −20 min and +20 min of recording). S1 and S2 represent independent afferents synapsing on basal or apical dendrites, respectively.</p