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

A molecular circuit composed of CPEB-1 and c-Jun controls growth hormone-mediated synaptic plasticity in the mouse hippocampus

Cytoplasmic polyadenylation element binding protein 1 (CPEB-1) resides at postsynaptic sites in hippocampal neurons in which it controls polyadenylation-induced translation. CPEB-1 knock-out (KO) mice display defects in some forms of synaptic plasticity and hippocampal-dependent memories. To identify CPEB-1-regulated mRNAs, we used proteomics to compare polypeptides in wild-type (WT) and CPEB-1 KO hippocampus. Growth hormone (GH) was reduced in the KO hippocampus, as were the GH signaling molecules phospho-JAK2 and phospho-STAT3. GH mRNA and pre-mRNA were reduced in the KO hippocampus, suggesting that CPEB-1 controls GH transcription. The transcription factor c-Jun, which binds the GH promoter, was also reduced in the KO hippocampus, as was its ability to coimmunoprecipitate chromatin containing the GH promoter. CPEB-1 binds c-Jun 3\u27 untranslated region CPEs in vitro and coimmunoprecipitates c-Jun RNA in vivo. GH induces long-term potentiation (LTP) when applied to hippocampal slices from WT and CPEB-1 KO mice, but the magnitude of LTP induced by GH in KO mice is reduced. Pretreatment with GH did not reverse the LTP deficit observed in KO mice after theta-burst stimulation (TBS). Cordycepin, an inhibitor of polyadenylation, disrupted LTP induced by either GH application or TBS. Finally, GH application to hippocampal slices induced JAK2 phosphorylation in WT but not KO animals. These results indicate that CPEB-1 control of c-Jun mRNA translation regulates GH gene expression and resulting downstream signaling events (e.g., synaptic plasticity) in the mouse hippocampus

Hyperdominance in Amazonian Forest Carbon Cycling

While Amazonian forests are extraordinarily diverse, the abundance of trees is skewed strongly towards relatively few ‘hyperdominant’ species. In addition to their diversity, Amazonian trees are a key component of the global carbon cycle, assimilating and storing more carbon than any other ecosystem on Earth. Here we ask, using a unique data set of 530 forest plots, if the functions of storing and producing woody carbon are concentrated in a small number of tree species, whether the most abundant species also dominate carbon cycling, and whether dominant species are characterized by specific functional traits. We find that dominance of forest function is even more concentrated in a few species than is dominance of tree abundance, with only ≈1% of Amazon tree species responsible for 50% of carbon storage and productivity. Although those species that contribute most to biomass and productivity are often abundant, species maximum size is also influential, while the identity and ranking of dominant species varies by function and by region

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

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

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

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

Dependency on transcription and protein synthesis inhibitors of the expression of LTD in the basal and apical dendritic compartments.

<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