Nonredundant Roles for CD1d-restricted Natural Killer T Cells and Conventional CD4+ T Cells in the Induction of Immunoglobulin E Antibodies in Response to Interleukin 18 Treatment of Mice

Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4+ T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d−/− mice that lack natural killer T (NKT) cells and in class II−/− mice that lack conventional CD4+ T cells. However, class II−/− mice reconstituted with conventional CD4+ T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)α chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4+ T cells express low levels of IL-18Rα and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4+ T cells are essential for B cell IgE responses after the administration of IL-18. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4+ T cells demonstrate their helper function in the presence of NKT cells

Genetic Deletion of NR3A Accelerates Glutamatergic Synapse Maturation

Glutamatergic synapse maturation is critically dependent upon activation of NMDA-type glutamate receptors (NMDARs); however, the contributions of NR3A subunit-containing NMDARs to this process have only begun to be considered. Here we characterized the expression of NR3A in the developing mouse forebrain and examined the consequences of NR3A deletion on excitatory synapse maturation. We found that NR3A is expressed in many subcellular compartments, and during early development, NR3A subunits are particularly concentrated in the postsynaptic density (PSD). NR3A levels dramatically decline with age and are no longer enriched at PSDs in juveniles and adults. Genetic deletion of NR3A accelerates glutamatergic synaptic transmission, as measured by AMPAR-mediated postsynaptic currents recorded in hippocampal CA1. Consistent with the functional observations, we observed that the deletion of NR3A accelerated the expression of the glutamate receptor subunits NR1, NR2A, and GluR1 in the PSD in postnatal day (P) 8 mice. These data support the idea that glutamate receptors concentrate at synapses earlier in NR3A-knockout (NR3A-KO) mice. The precocious maturation of both AMPAR function and glutamate receptor expression are transient in NR3A-KO mice, as AMPAR currents and glutamate receptor protein levels are similar in NR3A-KO and wildtype mice by P16, an age when endogenous NR3A levels are normally declining. Taken together, our data support a model whereby NR3A negatively regulates the developmental stabilization of glutamate receptors involved in excitatory neurotransmission, synaptogenesis, and spine growth

Nr3a-containing NMDA receptors promote neurotransmitter release and spike timing-dependent plasticity

Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the Nr3a subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that Nr3a is required for spike timing–dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, Nr2b-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that Nr3a relieves preNMDARs from the dual-activation requirement of ligand-binding and depolarization; the developmental removal of Nr3a limits preNMDAR functionality by restoring this associative property

MEF2C Enhances Dopaminergic Neuron Differentiation of Human Embryonic Stem Cells in a Parkinsonian Rat Model

Human embryonic stem cells (hESCs) can potentially differentiate into any cell type, including dopaminergic neurons to treat Parkinson's disease (PD), but hyperproliferation and tumor formation must be avoided. Accordingly, we use myocyte enhancer factor 2C (MEF2C) as a neurogenic and anti-apoptotic transcription factor to generate neurons from hESC-derived neural stem/progenitor cells (NPCs), thus avoiding hyperproliferation. Here, we report that forced expression of constitutively active MEF2C (MEF2CA) generates significantly greater numbers of neurons with dopaminergic properties in vitro. Conversely, RNAi knockdown of MEF2C in NPCs decreases neuronal differentiation and dendritic length. When we inject MEF2CA-programmed NPCs into 6-hydroxydopamine—lesioned Parkinsonian rats in vivo, the transplanted cells survive well, differentiate into tyrosine hydroxylase-positive neurons, and improve behavioral deficits to a significantly greater degree than non-programmed cells. The enriched generation of dopaminergic neuronal lineages from hESCs by forced expression of MEF2CA in the proper context may prove valuable in cell-based therapy for CNS disorders such as PD

Potential energy of hydrogen atom motion on Pd(111) surface and in subsurface: A first principles calculation

We calculate the adiabatic potential energy for hydrogen atom motion on a Pd(111) surface and in a subsurface within the framework of the density functional theory in order to understand the diffusion mechanism of a hydrogen atom from the Pd(111) surface to the subsurface. According to the calculated adiabatic potential energy surface for the hydrogen atom motion up to the third atom layer, an effective diffusion path of the hydrogen atom into the Pd bulk starts from the fcc hollow site on the Pd(111) surface. Moreover, the diffusion path passes through the octahedral site between the first and the second Pd atom layers, the tetrahedral site beneath a Pd atom of the first layer or above the Pd atom of the third layer, and the octahedral site between the second and third layer. © 2007 American Institute of Physics

Quantum states of hydrogen atom motion on the Pd(111) surface and in the subsurface

We investigate the quantum states of hydrogen atom motion on Pd(111) surface and in its subsurface by calculating the wavefunctions and the eigenenergies for hydrogen atom motion within the framework of the variation method on an adiabatic potential energy surface (PES), obtained through first-principles calculations, for the hydrogen atom motion. The calculated results show that the ground-state wavefunction for the hydrogen atom motion localizes on the face-centered cubic (fcc) hollow site of the surface. The higher excited state wavefunctions are distributed between the first and second layers, and subsequently delocalized under the second atom layer. These suggest that an effective diffusion path of the hydrogen atom into the subsurface area passes through the fcc hollow site to the octahedral sites in the subsurface. Moreover, activation energies for diffusion of H and D atoms over the saddle point of the PES between the fcc hollow site and the first (second) octahedral site are estimated as 598 (882)meV and 646 (939)meV, respectively. Furthermore, the activation energies for diffusion of H and D atoms over the saddle point of the PES between the first (second) octahedral site and the fcc hollow site are estimated as 285 (483)meV and 323 (532)meV, respectively. © IOP Publishing Ltd

Molecular Pathway to Protection From Age-Dependent Photoreceptor Degeneration in Mef2 Deficiency.

PurposePhotoreceptor degeneration in the retina is a major cause of blindness in humans. Elucidating mechanisms of degenerative and neuroprotective pathways in photoreceptors should afford identification and development of therapeutic strategies.MethodsWe used mouse genetic models and improved methods for retinal explant cultures. Retinas were enucleated from Mef2d+/+ and Mef2d-/- mice, stained for MEF2 proteins and outer nuclear layer thickness, and assayed for apoptotic cells. Chromatin immunoprecipitation (ChIP) assays revealed MEF2 binding, and RT-qPCR showed levels of transcription factors. We used AAV2 and electroporation to express genes in retinal explants and electroretinograms to assess photoreceptor functionality.ResultsWe identify a prosurvival MEF2D-PGC1α pathway that plays a neuroprotective role in photoreceptors. We demonstrate that Mef2d-/- mouse retinas manifest decreased expression of PGC1α and increased photoreceptor cell loss, resulting in the absence of light responses. Molecular repletion of PGC1α protects Mef2d-/- photoreceptors and preserves light responsivity.ConclusionsThese results suggest that the MEF2-PGC1α cascade may represent a new therapeutic target for drugs designed to protect photoreceptors from developmental- and age-dependent loss