NMDA Receptor Autoantibodies in Autoimmune Encephalitis Cause a Subunit-Specific Nanoscale Redistribution of NMDA Receptors

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

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Ferulic acid through mitigation of NMDA receptor pathway exerts anxiolytic-like effect in mouse model of maternal separation stress

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2019-0263 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Zahra Lorigooini ◽

Ali Nouri ◽

Faezeh mottaghinia ◽

Shima Balali-Dehkordi ◽

Elham Bijad ◽

...

Keyword(s):

Nmda Receptor ◽

Mouse Model ◽

Ferulic Acid ◽

Nmda Receptors ◽

Effective Dose ◽

Life Stress ◽

Receptor Agonist ◽

Maternal Separation ◽

Early Life Stress ◽

Central Zone

AbstractBackgroundExperiencing early-life stress plays an important role in the pathophysiology of anxiety disorders. Ferulic acid is a phenolic compound found in some plants which has several pharmacological properties. N-methyl-D-aspartate (NMDA) receptors are involved in the pathophysiology of mood disorders. In this study we aimed to assess the anxiolytic-like effect of ferulic acid in a mouse model of maternal separation (MS) stress by focusing on the possible involvement of NMDA receptors.MethodsMice were treated with ferulic acid (5 and 40 mg/kg) alone and in combination with NMDA receptor agonist/antagonist. Valid behavioral tests were performed, including open field test (OFT) and elevated plus maze test (EPM), while quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate gene expression of NMDA subunits (GluN2A and GluN2B) in the hippocampus.ResultsFindings showed that treatment of MS mice with ferulic acid increased the time spent in the central zone of the OFT and increased both open arm time and the percent of open arm entries in the EPM. Ferulic acid reduced the expression of NMDA receptor subunit genes. We showed that administration of NMDA receptor agonist (NMDA) and antagonist (ketamine) exerted anxiogenic and anxiolytic-like effects, correspondingly. Results showed that co-administration of a sub-effective dose of ferulic acid plus ketamine potentiated the anxiolytic-like effect of ferulic acid. Furthermore, co-administration of an effective dose of ferulic acid plus NMDA receptor agonist (NMDA) attenuated the anxiolytic-like effect of ferulic acid.ConclusionsIn deduction, our findings showed that NMDA, partially at least, is involved in the anxiolytic-like effect of ferulic acid in the OFT and EPM tests.

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Role of adenosine in NMDA receptor modulation in the cerebral cortex of an anoxia-tolerant turtle (Chrysemys picta belli).

Journal of Experimental Biology ◽

10.1242/jeb.198.7.1621 ◽

1995 ◽

Vol 198 (7) ◽

pp. 1621-1628 ◽

Cited By ~ 4

Author(s):

L T Buck ◽

P E Bickler

Keyword(s):

Cerebral Cortex ◽

Nmda Receptor ◽

Nmda Receptors ◽

Control Level ◽

Chrysemys Picta ◽

Receptor Modulation ◽

A1 Receptor ◽

Excitatory Neurotransmission ◽

Similar Decrease

Accumulation of the neuromodulator adenosine in the anoxia-tolerant turtle brain may play a key role in a protective decrease in excitatory neurotransmission during anoxia. Since excitatory neurotransmission is mediated largely by Ca2+ entry through N-methyl-D-aspartate (NMDA) receptors, we measured the effect of adenosine on NMDA-mediated Ca2+ transients in normoxic and anoxic turtle cerebrocortical sheets. Intracellular [Ca2+] was measured fluorometrically with the Ca2+-sensitive dye Fura-2. Baseline intracellular [Ca2+] and [ATP] were also measured to assess cortical sheet viability and potential toxic effects of NMDA. Baseline [Ca2+] did not change significantly under any condition, ranging from 109 +/- 22 to 187 +/- 26 nmoll-1. Throughout normoxic and 2h anoxic protocols, and after single and multiple NMDA exposures, [ATP] did not change significantly, ranging from 16.0 +/- 1.9 to 25.3 +/- 4.9 nmol ATP mg-1 protein. Adenosine caused a reduction in the normoxic NMDA-mediated increase in [Ca2+] from a control level of 287 +/- 35 to 103 +/- 22 nmoll-1 (64%). This effect is mediated by the A1 receptor since 8-phenyltheophylline (a specific A1 antagonist) effectively blocked the adenosine effect and N6-cyclopentyladenosine (a specific A1 agonist) elicited a similar decrease in the NMDA-mediated response. Cortical sheets exposed to anoxia alone exhibited a 52% decrease in the NMDA-mediated [Ca2+] rise, from 232 +/- 30 to 111 +/- 9 nmoll-1. The addition of adenosine had no further effect and 8-phenyltheophylline did not antagonize the observed decrease. Therefore, the observed down-regulation of NMDA receptor activity during anoxia must involve additional, as yet unknown, mechanisms.

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

Journal of Neurophysiology ◽

10.1152/jn.1990.63.5.1148 ◽

1990 ◽

Vol 63 (5) ◽

pp. 1148-1168 ◽

Cited By ~ 104

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)

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Frequency and temporal sequence of clinical features in adults with anti-NMDA receptor encephalitis presenting with psychiatric symptoms

Psychological Medicine ◽

10.1017/s0033291718003665 ◽

2018 ◽

Vol 49 (16) ◽

pp. 2709-2716 ◽

Cited By ~ 3

Author(s):

Ronald J. Gurrera

Keyword(s):

Nmda Receptor ◽

Clinical Features ◽

Psychiatric Symptoms ◽

Autoimmune Encephalitis ◽

Signs And Symptoms ◽

Nmda Receptor Encephalitis ◽

Nmdar Encephalitis ◽

Unexplained Fever ◽

Study Inclusion

AbstractBackgroundAnti-NMDA receptor (NMDAr) encephalitis is the most common autoimmune encephalitis in adults. It mimics psychiatric disorders so often that most patients are initially referred to a psychiatrist, and many are misdiagnosed. Without prompt and effective treatment, patients are likely to suffer a protracted course with significant residual disability, or death. This study focuses on the frequency and chronology of salient clinical features in adults with anti-NMDAr encephalitis who are likely to be first evaluated by a psychiatrist because their presentation suggests a primary psychiatric disorder.MethodsA systematic search of PubMed and EMBASE databases identified published reports of anti-NMDAr encephalitis associated with prominent behavioral or psychiatric symptoms. After eliminating redundancies, the frequencies and relative timing of clinical features were tabulated. Signs and symptoms were assigned temporal ranks based on the timing of their first appearance relative to the first appearance of other signs and symptoms in each patient; median ranks were used to compare temporal sequencing of both individual features and major symptom domains.ResultsTwo hundred thirty unique cases (185 female) met study inclusion criteria. The most common features were seizures (60.4%), disorientation/confusion (42.6%), orofacial dyskinesias (39.1%), and mutism/staring (37.4%). Seizures, fever, and cognitive dysfunction were often the earliest features to emerge, but psychiatric features predominated and sequencing varied greatly between individuals.ConclusionsClinicians should consider anti-NMDAr encephalitis when new psychiatric symptoms are accompanied by a recent viral prodrome, seizures or unexplained fever, or when the quality of the psychiatric symptoms is unusual (e.g. non-verbal auditory hallucinations).

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Role of N-methyl-D-aspartate receptors in the pontine pneumotaxic mechanism in the cat

Journal of Applied Physiology ◽

10.1152/jappl.1994.76.3.1138 ◽

1994 ◽

Vol 76 (3) ◽

pp. 1138-1143 ◽

Cited By ~ 45

Author(s):

L. Ling ◽

D. R. Karius ◽

D. F. Speck

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Partial Recovery ◽

Inspiratory Time ◽

Systemic Injection ◽

Lung Inflation ◽

Mk 801 ◽

Efferent Limb ◽

Adult Cats

Systemic injection of MK-801, an N-methyl-D-aspartate (NMDA) receptor-associated channel blocker, induces an apneusis in vagotomized cats similar to that produced by pontine respiratory group (PRG) lesions, suggesting the possible involvement of NMDA receptors in the pontine pneumotaxic mechanism. Previous results from our laboratory indicate that the efferent limb of the pontine pneumotaxic mechanism is unlikely to require NMDA receptor-mediated neurotransmission. Therefore, the present study examined the potential involvement of PRG NMDA receptors in the pontine pneumotaxic mechanism. Experiments were conducted in decerebrate, paralyzed, and ventilated adult cats. The effects on inspiratory time (TI) of MK-801 microinjection into PRG were tested in 12 cats. Pressure microinjection of MK-801 (15 mM, 80–3,000 nl) significantly prolonged TI in all animals when lung inflation was withheld. TI progressively increased in most animals for > or = 30 min. After this period, partial recovery of the effect occurred in eight cats as TI shortened toward predrug levels. In three animals, microinjection of MK-801 induced a complete apneusis in the absence of lung inflation from which there was no detectable recovery. Microinjections into regions approximately 2 mm distant from PRG produced little or no effect. These results provide evidence that NMDA receptors located in the region of PRG play an important functional role in the control of the breathing cycle.

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A Fast Synaptic Potential Mediated by NMDA and Non-NMDA Receptors

Journal of Neurophysiology ◽

10.1152/jn.1997.78.5.2693 ◽

1997 ◽

Vol 78 (5) ◽

pp. 2693-2706 ◽

Cited By ~ 23

Author(s):

Laura R. Wolszon ◽

Alberto E. Pereda ◽

Donald S. Faber

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Resting Potential ◽

Repetitive Firing ◽

Physiological Data ◽

Receptor Subtypes ◽

Excitatory Postsynaptic Potential ◽

Synaptic Potential ◽

Synaptic Currents ◽

Fast Kinetics

Wolszon, Laura R., Alberto E. Pereda, and Donald S. Faber. A fast synaptic potential mediated by NMDA and non-NMDA receptors. J. Neurophysiol. 78: 2693–2706, 1997. Excitatory synaptic transmission in the CNS often is mediated by two kinetically distinct glutamate receptor subtypes that frequently are colocalized, the N-methyl-d-aspartate (NMDA) and non-NMDA receptors. Their synaptic currents are typically very slow and very fast, respectively. We examined the pharmacological and physiological properties of chemical excitatory transmission at the mixed electrical and chemical synapses between auditory afferents and the goldfish Mauthner cell, in vivo. Previous physiological data have suggested the involvement of glutamate receptors in this fast excitatory postsynaptic potential (EPSP), the chemical component of which decays with a time constant of <2 ms. We demonstrate here that the pharmacological and voltage-dependent characteristics of the synaptic currents are consistent with glutamatergic transmission and that both NMDA and non-NMDA receptors are involved. The two components surprisingly exhibit quite similar kinetics even at resting potential, with the NMDA response being only slightly slower. Due to its fast kinetics and characteristic voltage dependence, NMDA receptor-mediated transmission at these first-order synapses contributes significantly to paired pulse and frequency-dependent facilitation of successive fast EPSPs during high-frequency repetitive firing, a presynaptic impulse pattern that induces activity-dependent homosynaptic changes in both electrical and chemical transmission. Thus NMDA receptor kinetics in this intact preparation are suited to its functional requirements, namely speed of information transmission and the ability to trigger changes in synaptic efficacy.

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Glycine regulation of synaptic NMDA receptors in hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1996.76.5.3415 ◽

1996 ◽

Vol 76 (5) ◽

pp. 3415-3424 ◽

Cited By ~ 48

Author(s):

K. S. Wilcox ◽

R. M. Fitzsimonds ◽

B. Johnson ◽

M. A. Dichter

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Hippocampal Neurons ◽

Time Course ◽

Hippocampal Slices ◽

Maximal Effect ◽

Patch Clamp Technique ◽

Whole Cell Patch Clamp ◽

Dissociated Cell Culture ◽

Cultured Hippocampal Neurons

1. Although glycine has been identified as a required coagonist with glutamate at N-methyl-D-aspartate (NMDA) receptors, the understanding of glycine's role in excitatory synaptic neurotransmission is quite limited. In the present study, we used the whole cell patch-clamp technique to examine the ability of glycine to regulate current flow through synaptic NMDA receptors at excitatory synapses between cultured hippocampal neurons and in acutely isolated hippocampal slices. 2. These studies demonstrate that the glycine modulatory site on the synaptic NMDA receptor is not saturated under baseline conditions and that increased glycine concentrations can markedly increased NMDA-receptor-mediated excitatory postsynaptic currents (EPSCs) in hippocampal neurons in both dissociated cell culture and in slice. Saturation of the maximal effect of glycine takes place at different concentrations for different cells in culture, suggesting the presence of heterogenous NMDA receptor subunit compositions. 3. Bath-applied glycine had no effect on the time course of EPSCs in either brain slice or culture, indicating that desensitization of the NMDA receptor is not prevented by glycine over the time course of an EPSC. 4. When extracellular glycine concentration is high, all miniature EPSCs recorded in the cultured hippocampal neurons contained NMDA components, indicating that segregation of non-NMDA receptors at individual synaptic boutons does not occur.

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PACAP38 Modulates Activity of NMDA Receptors in Cultured Chick Cortical Neurons

Journal of Neurophysiology ◽

10.1152/jn.1997.78.4.2231 ◽

1997 ◽

Vol 78 (4) ◽

pp. 2231-2234 ◽

Cited By ~ 26

Author(s):

Guo Jun Liu ◽

Barry W. Madsen

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Cortical Neurons ◽

Second Messengers ◽

Channel Activity ◽

Patch Clamp Technique ◽

Low Concentrations ◽

Channel Opening ◽

Pituitary Adenylate Cyclase ◽

Intracellular Second Messengers

Liu, Guo Jun and Barry W. Madsen. PACAP38 modulates activity of NMDA receptors in cultured chick cortical neurons. J. Neurophysiol. 78: 2231–2234, 1997. The outside-out recording mode of the patch-clamp technique was used to study modulatory effects of pituitary adenylate cyclase-activating polypeptide (PACAP38) on N-methyl-d-aspartate (NMDA) receptor activity in cultured chick cortical neurons. Biphasic concentration-dependent effects of PACAP38 on channel opening frequency induced by NMDA (20 μM) and glycine (1 μM) were found, with low concentrations (0.5–2 nM) of PACAP38 increasing activity and higher concentrations (10–1,000 nM) causing inhibition. These effects were reversible, reduced with higher concentrations of glycine (2–10 μM) but not by 200 μM NMDA, and inhibited by 10 μM 7-chlorokynurenic acid. In addition, 1 μM PACAP6–38 (a PACAP antagonist) inhibited channel activity due to 20 μM NMDA and 1 μM glycine by 66%, and this inhibition was reduced to 13% in the additional presence of 2 nM PACAP38. These observations suggest thatPACAP38 has a direct modulatory effect on the NMDA receptor that is independent of intracellular second messengers and probably mediated through the glycine coagonist site(s).

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Safety of Cholinesterase Inhibitors and NMDA Receptors Antagonists for the Treatment of Patients with Dementia

Safety and Risk of Pharmacotherapy ◽

10.30895/2312-7821-2019-7-4-190-199 ◽

2019 ◽

Vol 7 (4) ◽

pp. 190-199

Author(s):

A. P. Pereverzev ◽

O. D. Ostroumova ◽

O. N. Tkacheva ◽

Y. V. Kotovskaya

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Adverse Drug Reactions ◽

Cholinesterase Inhibitors ◽

Acetylcholinesterase Inhibitors ◽

Competitive Inhibitor ◽

Nmda Receptor Antagonists ◽

Drug Reactions ◽

Receptor Antagonists ◽

Increased Risk

For the treatment of dementia and Alzheimer’s disease, acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or the non-competitive inhibitor of N-methyl-D-aspartate receptors (NMDA receptors) memantine are currently used. The administration of these drugs can help temporarily improve or stabilize memory impairments and other cognitive functions, regress behavioral disorders, reduce the patient’s dependence on others, but at the same time can lead to the development of adverse drug reactions. The aim of this study was to analyze the information on the safety of acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the non-competitive inhibitor of NMDA receptors used to treat dementia. It was shown that stimulation of cholinergic receptors can lead to adverse drug reactions as contraction and narrowing of the pupil (miosis), an increase in lens curvature, accommodation spasm (visual impairment and an increased risk of falls), a decrease in heart rate (bradycardia) and inhibition of conduction of impulses through the conducting system heart, increased tone of the bronchi, gastrointestinal tract, gall and bladder, decreased tone of the sphincters of the digestive tract and bladder, increased secretion of exocrine and glands of the stomach, agitation, confusion. Blockade of NMDA receptors due to impairment of glutamate metabolism in the central nervous system may be the cause of neurotoxicity of NMDA receptor antagonists, and also causes dizziness, feeling of tiredness, hallucinations, drowsiness, and confusion. In case of development of adverse reactions, if possible, it is necessary to stop using the drug or reduce its dose, in case of an overdose or other need, prescribe symptomatic therapy. Information on the safety of cholinesterase inhibitors and NMDA receptor antagonists presented in the article is of practical importance for healthcare professionals, as it allows them to assess the possible risks associated with the use of drugs of these groups more accurately. In addition, the information can be used to optimize and individualize the pharmacotherapy regimens for patients with dementia, including the development of domestic protocols for the deprescribing of drugs (evidence-based practice of withdrawal, replacement or gradual dose reduction) in the elderly.

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