279 Numerous observational and correlative studies suggest that alloantibodies may contribute to acute and chronic rejection of organ allografts. In our previous studies we documented that the total elimination of alloantibody responses inhibits cardiac rejection in mice. The acute rejection (7-10 days) of B10.A (H-2a), B10.BR (H-2k), B10.D2 (H-2d) cardiac allografts in wild type (WT) C57BL/6 (H-2b) recipients was inhibited in C57BL-Igh-6, Ig knock out (IgKO) mice, in which grafts survived more than 50 days after transplantation (n=8-15/group). The present study was undertaken to further analyze the mechanism of alloantibody-mediated graft injury in the model of B10.A cardiac allografts in WT and IgKO C57BL/6 recipients (n=19). The rejection of B10.A hearts was characterized by intense interstitial and perivascular cellular infiltration; very strong IgG, IgM, complement (C) deposition; and vascular injury. In IgKO recipients these signs of rejection were decreased significantly. Activation of endothelial cells and platelets was decreased in the absence of alloantibody responses. In WT recipients, platelet aggregates were attached to arterial walls and occluded capillaries. Immunohistology demonstrated von Willebrand's factor in these platelet aggregates. In contrast, von Willebrand's factor remained in cytoplasmic storage granules of endothelial cells and fewer platelet aggregates were found in IgKO recipients. Semiquantitative competitive template RT-PCR on the cardiac transplants demonstrated similar levels of IL-1, IL-12, TNF-α, IL-2, and IFN-γ mRNA in WT and IgKO recipients 10-15 days after transplantation, indicating that macrophage- and T-cell-dependent immune responses were intact in IgKO recipients. Passive transfer of IgG2a and IgG2b monoclonal antibodies (mAbs) against donor H-2a MHC (300 μg, i.v.) to IgKO recipients 10 days after transplantation caused rejection of cardiac allografts within 1-2 days (n=4). Recipients injected with the same dose of isotype-matched control mAbs did not reject (n=3). Immunofluorescence staining demonstrated intense deposition of IgG and C in rejected hearts, and flow cytometry analysis demonstrated the presence of both injected IgG2a and IgG2b mAbs in the circulation. Taken together these data offer direct evidence that alloantibodies are critical to the process of acute cardiac rejection and pathogenesis of vascular lesions in certain strain combinations.
Abstract Ionic currents, whether measured as conductance amplitude or as ion channel transcript levels, can vary many-fold within a population of identified neurons. This variability has been observed in multiple invertebrate neuronal types, but they do so in a coordinated manner such that their magnitudes are correlated. These conductance correlations are thought to reflect a tight homeostasis of cellular excitability that enhances the robustness and stability of neuronal activity over long stretches of time. Notably, although such ionic current correlations are well documented in invertebrates, they have not been reported in vertebrates. Here we demonstrate with two examples, identified mouse hippocampal granule cells and cholinergic basal forebrain neurons, that ionic current correlations is a ubiquitous phenomenon expressed by a number of species across phyla.
Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca(2+) channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.Bidirectional changes of synaptic strength are crucial for the encoding of new memories. Currently, the only activity-dependent mechanism known to support such bidirectional changes are long-term potentiation (LTP) and long-term depression (LTD) forms that relay on the activation of NMDA receptors. Metabotropic glutamate receptors (mGluRs) are, in principle, also suitable to trigger bidirectional synaptic modifications. However, only the mGluR-dependent form of LTD has been characterized. Here we report that an NMDAR-independent form of LTP, initially characterized as dependent on voltage-gated Ca(2+) channels, also requires the activation of mGluRs. These finding suggest the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.
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