scholarly journals Blocking Placental Class G Immunoglobulin Transfer Prevents NMDA Receptor Antibody Effects in Newborn Mice

2021 ◽  
Vol 8 (6) ◽  
pp. e1061
Author(s):  
Anna García-Serra ◽  
Marija Radosevic ◽  
José Ríos ◽  
Esther Aguilar ◽  
Estibaliz Maudes ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Placental Transfer ◽  
Plate Thickness ◽  
Fetal Brain ◽  
Long Term Potentiation ◽  
Cortical Plate ◽  
Newborn Mice ◽  
Therapeutic Implications ◽  
Nmdar Encephalitis ◽  
Pregnant Mice

Background and ObjectivesTo determine in a mouse model whether neonatal Fc receptor (FcRn) blockade prevents the placental transfer of class G immunoglobulin (IgG) derived from patients with anti-NMDA receptor (NMDAR) encephalitis and their pathogenic effects on the fetuses and offspring.MethodsPregnant C57BL/6J mice were administered via tail vein FcRn antibody (FcRn-ab) or saline solution 6 hours before administration of patients' or controls' IgG on days 14, 15, and 16 of gestation. Three experimental groups were established: mice receiving controls' IgG, patients' IgG, or patients' IgG along with pretreatment with FcRn-ab. Immunohistochemical staining, confocal microscopy, hippocampal long-term potentiation, and standardized developmental and behavioral tasks were used to assess the efficacy of treatment with FcRn-ab.ResultsIn pregnant mice that received patients' IgG, treatment with FcRn-ab prevented the IgG from reaching the fetal brain, abrogating the decrease of NMDAR clusters and the reduction of cortical plate thickness that were observed in fetuses from untreated pregnant mice. Moreover, among the offspring of mothers that received patients' IgG, those whose mothers were treated with FcRn-ab did not develop the alterations that occurred in offspring of untreated mothers, including impairment in hippocampal plasticity, delay in innate reflexes, and visuospatial memory deficits.DiscussionFcRn blockade prevents placental transfer of IgG from patients with anti-NMDAR encephalitis and abrogates the synaptic and neurodevelopmental alterations caused by patients' antibodies. This model has potential therapeutic implications for other antibody-mediated diseases of the CNS during pregnancy.

scholarly journals Placental transfer of NMDAR antibodies causes reversible alterations in mice

2020 ◽  
Vol 8 (1) ◽  
pp. e915
Author(s):  
Anna García-Serra ◽  
Marija Radosevic ◽  
Anika Pupak ◽  
Veronica Brito ◽  
José Ríos ◽  
...  
Keyword(s):  
Motor Coordination ◽  
Placental Transfer ◽  
Plate Thickness ◽  
Long Term Potentiation ◽  
Cortical Plate ◽  
Term Potentiation ◽  
Dye Staining ◽  
Eye Opening ◽  
Antibody Effects

ObjectiveTo determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies.MethodsPregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14–16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects.ResultsIn brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II–IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood.ConclusionsIn this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy.

Metabotropic glutamate receptor dependent EPSP and EPSP-spike potentiation in area CA1 of the submerged rat hippocampal slice

1996 ◽  
Vol 76 (5) ◽  
pp. 3126-3135 ◽  
Author(s):  
N. A. Breakwell ◽  
M. J. Rowan ◽  
R. Anwyl
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Cell Body ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Excitatory Postsynaptic Potential ◽  
Area Ca1 ◽  
Gabaa Receptor Antagonist

1. We reexamined the important areas of conflict in (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]-induced potentiation of the field excitatory postsynaptic potential (EPSP) and, for the first time, investigated the role of mGluRs in EPSP-spike (E-S) coupling. 2. (1S,3R)-ACPD (10 microM) bath applied for 20 min consistently induced a long-lasting potentiation of the dendritic EPSP in area CA1 of submerged rat hippocampal slices, which was considerably faster in onset than described previously. 3. This effect was not associated with any change in presynaptic fiber volley but was dependent on both an intact CA3 connection, because removal of area CA3 blocked (1S,3R)-ACPD-induced potentiation, and also on functional N-methyl-D-aspartate (NMDA) receptors, because (1S,3R)-ACPD-induced potentiation was blocked by inclusion of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP5; 50 microM). 4. (1S,3R)-ACPD induced a long-lasting potentiation of the population spike (PS) amplitude that was consistently larger than that of the EPSP measured in the cell body area. This EPSP-PS (E-S) potentiation was blocked by inclusion of the gamma-aminobuturic acid-A (GABAA) receptor antagonist, picrotoxin (50 microM). 5. E-S potentiation induced by high-frequency stimulation (HFS), which was of the same magnitude as that induced by (1S,3R)-ACPD, was blocked by the mGluR-selective antagonist (+)-alpha-methyl-4-carboxyphenylglycine (+MCPG; 250 microM). +MCPG also blocked HFS-induced long-term potentiation (LTP) of the EPSP measured in the cell body. 6. These results suggest that (1S,3R)-ACPD-induced potentiation is NMDA receptor dependent, contrary to some previous findings, and provide further evidence that both synaptic and E-S potentiation induced by (1S,3R)-ACPD share common mechanisms of expression with HFS-induced LTP. The data emphasize the important role of mGluRs in induction of EPSP LTP and E-S potentiation.

scholarly journals Phylogenetic Analysis to Explore the Association Between Anti-NMDA Receptor Encephalitis and Tumors Based on microRNA Biomarkers

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 572 ◽  
Author(s):  
Wang
Keyword(s):  
Phylogenetic Analysis ◽  
Nmda Receptor ◽  
Phylogenetic Trees ◽  
Tumor Resection ◽  
Autoimmune Disorder ◽  
Control Of Gene Expression ◽  
Nmda Receptor Encephalitis ◽  
Nmdar Encephalitis ◽  
Non Coding Rna ◽  
The Relationship

MicroRNA (miRNA) is a small non-coding RNA that functions in the epigenetics control of gene expression, which can be used as a useful biomarker for diseases. Anti-NMDA receptor (anti-NMDAR) encephalitis is an acute autoimmune disorder. Some patients have been found to have tumors, specifically teratomas. This disease occurs more often in females than in males. Most of them have a significant recovery after tumor resection, which shows that the tumor may induce anti-NMDAR encephalitis. In this study, I review microRNA (miRNA) biomarkers that are associated with anti-NMDAR encephalitis and related tumors, respectively. To the best of my knowledge, there has not been any research in the literature investigating the relationship between anti-NMDAR encephalitis and tumors through their miRNA biomarkers. I adopt a phylogenetic analysis to plot the phylogenetic trees of their miRNA biomarkers. From the analyzed results, it may be concluded that (i) there is a relationship between these tumors and anti-NMDAR encephalitis, and (ii) this disease occurs more often in females than in males. This sheds light on this issue through miRNA intervention.

scholarly journals Defective place cell activity in nociceptin receptor knockout mice with elevated NMDA receptor-dependent long-term potentiation

2005 ◽  
Vol 565 (2) ◽  
pp. 579-591 ◽  
Author(s):  
Franco A. Taverna ◽  
John Georgiou ◽  
Robert J. McDonald ◽  
Nancy S. Hong ◽  
Alexander Kraev ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Knockout Mice ◽  
Cell Activity ◽  
Long Term Potentiation ◽  
Place Cell ◽  
Term Potentiation ◽  
Nociceptin Receptor

Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory

2008 ◽  
Vol 31 (2) ◽  
pp. 250-260 ◽  
Author(s):  
Chanel J. Taylor ◽  
David R. Ireland ◽  
Irene Ballagh ◽  
Katie Bourne ◽  
Nicola M. Marechal ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Spatial Memory ◽  
Amyloid Precursor Protein ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Receptor Function ◽  
Term Potentiation ◽  
Nmda Receptor Function

Newborn Screening for Congenital Hypothyroidism: Recommended Guidelines

PEDIATRICS ◽  
1993 ◽  
Vol 91 (6) ◽  
pp. 1203-1209
Author(s):  
Keyword(s):  
Thyroid Hormone ◽  
Newborn Screening ◽  
Congenital Hypothyroidism ◽  
Placental Transfer ◽  
Fetal Brain ◽  
Iodothyronine Deiodinase ◽  
Screening Programs ◽  
Organ Systems ◽  
Fetal Hypothyroidism ◽  
Maternal Thyroid

Congenital hypothyroidism (CH) represents one of the most common preventable causes of mental retardation. The fetal hypothalamic-pituitary-thyroid axis begins to function by midgestation and is mature in the term infant at delivery. If fetal hypothyroidism develops, untoward effects may be demonstrated in certain organ systems, including the central nervous system and skeleton. However, most infants with CH appear normal at birth. Recent data suggest that the hypothyroid fetus is protected to a certain extent by placental transfer of maternal thyroid hormone; serum thyroxine (T4) levels in the cord blood of athyroid fetuses approximate one third of maternal levels.1 In addition, studies in animal models of hypothyroidism demonstrate increased levels of brain iodothyronine deiodinase, the enzyme which converts T4 to triiodothyronine (T3). In the hypothyroid fetus, this increased enzyme acting on T4 of maternal origin is sufficient to produce near normal fetal brain T3 concentrations.2 Thus, it appears that early detection and treatment of congenital hypothyroidism should have the potential to completely reverse the effects of fetal hypothyroidism in all but the most severe cases, for example, athyreotic infants born to mothers with thyroid problems resulting in inadequate placental transfer of maternal thyroid hormone. Since the development of pilot screening programs for CH in Quebec and Pittsburgh in 1974,3 newborn screening for CH has become routine in essentially all developed countries of the world and is under development in Eastern Europe, South America, Asia, and Africa. In North America it is estimated that more than 5 million newborns are screened, with approximately 1400 infants with congenital hypothyroidism detected annually.

Insights into associative long-term potentiation from computational models of NMDA receptor-mediated calcium influx and intracellular calcium concentration changes

1990 ◽  
Vol 63 (5) ◽  
pp. 1148-1168 ◽  
Author(s):  
W. R. Holmes ◽  
W. B. Levy
Keyword(s):  
Experimental Data ◽  
Nmda Receptor ◽  
Nmda Receptors ◽  
Dendritic Spine ◽  
Long Term Potentiation ◽  
Input Frequency ◽  
Spine Head ◽  
Term Potentiation ◽  
Concentration Changes

1. Because induction of associative long-term potentiation (LTP) in the dentate gyrus is thought to depend on Ca2+ influx through channels controlled by N-methyl-D-aspartate (NMDA) receptors, quantitative modeling was performed of synaptically mediated Ca2+ influx as a function of synaptic coactivation. The goal was to determine whether Ca2+ influx through NMDA-receptor channels was, by itself, sufficient to explain associative LTP, including control experiments and the temporal requirements of LTP. 2. Ca2+ influx through NMDA-receptor channels was modeled at a synapse on a dendritic spine of a reconstructed hippocampal dentate granule cell when 1-115 synapses on spines at different dendritic locations were activated eight times at frequencies of 10-800 Hz. The resulting change in [Ca2+] in the spine head was estimated from the Ca2+ influx with the use of a model of a dendritic spine that included Ca2+ buffers, pumps, and diffusion. 3. To use a compelling model of synaptic activation, we developed quantitative descriptions of the NMDA and non-NMDA receptor-mediated conductances consistent with available experimental data. The experimental data reported for NMDA and non-NMDA receptor-channel properties and data from other non-LTP experiments that separated the NMDA and non-NMDA receptor-mediated components of synaptic events proved to be limiting for particular synaptic variables. Relative to the non-NMDA glutamate-type receptors, 1) the unbinding of transmitter from NMDA receptors had to be slow, 2) the transition from the bound NMDA receptor-transmitter complex to the open channel state had to be even slower, and 3) the average number of NMDA-receptor channels at a single activated synapse on a single spine head that were open and conducting at a given moment in time had to be very small (usually less than 1). 4. With the use of these quantitative synaptic conductance descriptions. Ca2+ influx through NMDA-receptor channels at a synapse was computed for a variety of conditions. For a constant number of pulses, Ca2+ influx was calculated as a function of input frequency and the number of coactivated synapses. When few synapses were coactivated, Ca2+ influx was small, even for high-frequency activation. However, with larger numbers of coactivated synapses, there was a steep increase in Ca2+ influx with increasing input frequency because of the voltage-dependent nature of the NMDA receptor-mediated conductance. Nevertheless, total Ca2+ influx was never increased more than fourfold by increasing input frequency or the number of coactivated synapses.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Intracellular Domains of NMDA Receptor Subtypes Are Determinants for Long-Term Potentiation Induction

2003 ◽  
Vol 23 (34) ◽  
pp. 10791-10799 ◽  
Author(s):  
Georg Köhr ◽  
Vidar Jensen ◽  
Helmut J. Koester ◽  
Andre L. A. Mihaljevic ◽  
Jo K. Utvik ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Long Term Potentiation ◽  
Receptor Subtypes ◽  
Term Potentiation ◽  
Intracellular Domains
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