scholarly journals Higher Seizure Susceptibility and Enhanced Tyrosine Phosphorylation of N-Methyl-d-Aspartate Receptor Subunit 2B in fyn Transgenic Mice

1998 ◽  
Vol 5 (6) ◽  
pp. 429-445 ◽  
Author(s):  
Nobuhiko Kojima ◽  
Hidetoshi Ishibashi ◽  
Kunihiko Obata ◽  
Eric R. Kandel
Keyword(s):  
Nmda Receptor ◽  
Transgenic Mice ◽  
Tyrosine Phosphorylation ◽  
Neuronal Plasticity ◽  
Seizure Activity ◽  
Nmda Receptor Antagonist ◽  
Wild Type ◽  
Once Daily ◽  
Aspartate Receptor ◽  
Stimulation Of

Earlier work has suggested that Fyn tyrosine kinase plays an important role in synaptic plasticity. To understand the downstream targets of Fyn signaling cascade in neurons, we generated transgenic mice expressing either a constitutively activated form of Fyn or native Fyn in neurons of the forebrain. Transgenic mice expressing mutant Fyn exhibited higher seizure activity and were prone to sudden death. Mice overexpressing native Fyn did not show such an obvious epileptic phenotype, but they exhibited accelerated kindling in response to once-daily stimulation of the amygdala. Tyrosine phosphorylation of at least three proteins was enhanced in the forebrains of both native and mutant fyn transgenic mice; tyrosine phosphorylation of these three proteins was reduced infyn knockout mice, suggesting that they are substrates of Fyn. One of these proteins was identified as the subunit 2B (NR2B) of theN-methyl-d-aspartate (NMDA) receptor. Administration of MK-801, a noncompetitive NMDA receptor antagonist, retarded kindling in mice overexpressing native Fyn, as well as wild-type mice, suggests that the accelerated kindling in mice overexpressing Fyn is also mediated by the NMDA receptor activity. Our results thus suggest that tyrosine phosphorylation by Fyn might be involved in regulation of the susceptibility of kindling, one form of the NMDA receptor-mediated neuronal plasticity.

Excitatory transmission in the basolateral amygdala

1991 ◽  
Vol 66 (3) ◽  
pp. 986-998 ◽  
Author(s):  
D. G. Rainnie ◽  
E. K. Asprodini ◽  
P. Shinnick-Gallagher
Keyword(s):  
Nmda Receptor ◽  
Receptor Antagonist ◽  
Nmda Antagonist ◽  
Receptor Activation ◽  
Nmda Receptor Antagonist ◽  
Current Injection ◽  
Membrane Hyperpolarization ◽  
Postsynaptic Potentials ◽  
The Mean ◽  
Stimulation Of

1. Intracellular current-clamp recordings obtained from neurons of the basolateral nucleus of the amygdala (BLA) were used to characterize postsynaptic potentials elicited through stimulation of the stria terminalis (ST) or the lateral amygdala (LA). The contribution of glutamatergic receptor subtypes to excitatory postsynaptic potentials (EPSPs) were analyzed by the use of the non N-methyl-D-aspartate (non-NMDA) antagonist, 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), and the NMDA antagonist, (DL)-2-amino-5-phosphonovaleric acid (APV). 2. Basic membrane properties of BLA neurons determined from membrane responses to transient current injection showed that at the mean resting membrane potential (RMP; -67.2 mV) the input resistance (RN) and time constant for membrane charging (tau) were near maximal, and that both values were reduced with membrane hyperpolarization, suggesting an intrinsic regulation of synaptic efficacy. 3. Responses to stimulation of the ST or LA consisted of an EPSP followed by either a fast inhibitory postsynaptic potential (f-IPSP) only, or by a fast- and subsequent slow-IPSP (s-IPSP). The EPSP was graded in nature, increasing in amplitude with increased stimulus intensity, and with membrane hyperpolarization after DC current injection. Spontaneous EPSPs were also observed either as discrete events or as EPSP/IPSP waveforms. 4. In physiological Mg2+ concentrations (1.2 mM), at the mean RMP, the EPSP consisted of dual, fast and slow, glutamatergic components. The fast-EPSP (f-EPSP) possessed characteristics of kainate/quisqualate receptor activation, namely, the EPSP increased in amplitude with membrane hyperpolarization, was insensitive to the NMDA receptor antagonist, APV (50 microM), and was blocked by the non-NMDA receptor antagonist, CNQX (10 microM). In contrast, the slow-EPSP (s-EPSP) decreased in amplitude with membrane hyperpolarization, was insensitive to CNQX (10 microM), and was blocked by APV (50 microM), indicating mediation by NMDA receptor activation. 5. In the presence of CNQX (10 microM), ST stimulation evoked an APV-sensitive s-EPSP. In contrast, LA stimulation evoked a f-IPSP, which when blocked by subsequent addition of bicuculline methiodide (BMI; 30 microM) revealed a temporally overlapping APV-sensitive s-EPSP. These data suggest that EPSP amplitude and duration are determined, in part, by the shunting of membrane conductance caused by a concomitant IPSP. 6. Superfusion of either CNQX or APV in BLA neurons caused membrane hyperpolarization and blockade of spontaneous EPSPs and IPSPs, suggesting that these compounds may act to block tonic excitatory amino acid (EAA) release within the nucleus, and that a degree of feed-forward inhibition occurs within the nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of the medullary lateral tegmental field in reflex-mediated sympathoexcitation in cats

2004 ◽  
Vol 286 (3) ◽  
pp. R451-R464 ◽  
Author(s):  
Hakan S. Orer ◽  
Gerard L. Gebber ◽  
Shaun W. Phillips ◽  
Susan M. Barman
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Sympathetic Nerve Activity ◽  
Nmda Receptor Antagonist ◽  
Vagal Afferents ◽  
Reflex Pathways ◽  
Excitatory Responses ◽  
Stimulation Of

We tested the hypothesis that blockade of N-methyl-d-aspartate (NMDA) and non-NMDA receptors on medullary lateral tegmental field (LTF) neurons would reduce the sympathoexcitatory responses elicited by electrical stimulation of vagal, trigeminal, and sciatic afferents, posterior hypothalamus, and midbrain periaqueductal gray as well as by activation of arterial chemoreceptors with intravenous NaCN. Bilateral microinjection of a non-NMDA receptor antagonist into LTF of urethane-anesthetized cats significantly decreased vagal afferent-evoked excitatory responses in inferior cardiac and vertebral nerves to 29 ± 8 and 24 ± 6% of control ( n = 7), respectively. Likewise, blockade of non-NMDA receptors significantly reduced chemoreceptor reflex-induced increases in inferior cardiac (from 210 ± 22 to 129 ± 13% of control; n = 4) and vertebral nerves (from 253 ± 41 to 154 ± 20% of control; n = 7) and mean arterial pressure (from 39 ± 7 to 21 ± 5 mmHg; n = 8). Microinjection of muscimol, but not an NMDA receptor antagonist, caused similar attenuation of these excitatory responses. Sympathoexcitatory responses to the other stimuli were not attenuated by microinjection of a non-NMDA receptor antagonist or muscimol into LTF. In fact, excitatory responses elicited by stimulation of trigeminal, and in some cases sciatic, afferents were enhanced. These data reveal two new roles for the LTF in control of sympathetic nerve activity in cats. One, LTF neurons are involved in mediating sympathoexcitation elicited by activation of vagal afferents and arterial chemoreceptors, primarily via activation of non-NMDA receptors. Two, non-NMDA receptor-mediated activation of other LTF neurons tonically suppresses transmission in trigeminal-sympathetic and sciatic-sympathetic reflex pathways.

scholarly journals Are Altered Excitatory Synapses Found in Neuronal Migration Disorders?

2005 ◽  
Vol 5 (5) ◽  
pp. 171-173
Author(s):  
F. Edward Dudek
Keyword(s):  
Nmda Receptor ◽  
Knockout Mice ◽  
Neuronal Migration ◽  
Granule Cells ◽  
Seizure Activity ◽  
Mossy Fiber ◽  
Pyramidal Cells ◽  
Synaptic Response ◽  
Wild Type ◽  
Neuronal Migration Disorders

Physiological and Morphological Characterization of Dentate Granule Cells in the p35 Knock-out Mouse Hippocampus: Evidence for an Epileptic Circuit Patel LS, Wenzel HJ, Schwartzkroin PA J Neurosci 2004;24:9005–9014 There is a high correlation between pediatric epilepsies and neuronal migration disorders. What remains unclear is whether intrinsic features of the individual dysplastic cells give rise to heightened seizure susceptibility, or whether these dysplastic cells contribute to seizure activity by establishing abnormal circuits that alter the balance of inhibition and excitation. Mice lacking a functional p35 gene provide an ideal model in which to address these questions, because these knockout animals not only exhibit aberrant neuronal migration but also demonstrate spontaneous seizures. Extracellular field recordings from hippocampal slices, characterizing the input–output relation in the dentate, revealed little difference between wild-type and knockout mice under both normal and elevated extracellular potassium conditions. However, in the presence of the GABAA antagonist bicuculline, p35 knockout slices, but not wild-type slices, exhibited prolonged depolarizations in response to stimulation of the perforant path. No significant differences were found in the intrinsic properties of dentate granule cells (i.e., input resistance, time constant, action-potential generation) from wild-type versus knockout mice. However, antidromic activation (mossy fiber stimulation) evoked an excitatory synaptic response in more than 65% of granule cells from p35 knockout slices that was never observed in wild-type slices. Ultrastructural analyses identified morphological substrates for this aberrant excitation: recurrent axon collaterals, abnormal basal dendrites, and mossy fiber terminals forming synapses onto the spines of neighboring granule cells. These studies suggest that granule cells in p35 knockout mice contribute to seizure activity by forming an abnormal excitatory feedback circuit. Prolonged NMDA-mediated Synaptic Response, Altered Ifenprodil Sensitivity, and Generation of Epileptiform-like Events in a Malformed Hippocampus of Rats Exposed to Methylazoxymethanol in Utero Calcagnotto ME, Baraban SC J Neurophysiol 2005 [Epub ahead of print] Cortical malformations are often associated with refractory epilepsy and cognitive deficit. Clinical and experimental studies have demonstrated an important role for glutamate-mediated synaptic transmission in these conditions. With whole-cell voltage-clamp techniques, we examined evoked glutamate-mediated excitatory postsynaptic currents (eEPSCs) and responses to exogenously applied glutamate on hippocampal heterotopic cells in an animal model of malformation (i.e., rats exposed to methylazoxymethanol [MAM] in utero). Analysis of eEPSCs revealed that the late N-methyl-D-aspartate (NMDA) receptor–mediated eEPSC component was significantly increased on heterotopic cells compared with age-matched normotopic pyramidal cells. At a holding potential of +40 mV, heterotopic cells also exhibited eEPSCs with a slower decay-time constant. No differences in the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) component of eEPSCs were detected. In 23% of heterotopic pyramidal cells, electrical stimulation evoked prolonged burstlike responses. Focal application of glutamate (10 m M) targeted to different sites near the heterotopia also evoked epileptiform-like bursts on heterotopic cells. Ifenprodil (10 μM), an NR2B subunit antagonist, only slightly reduced the NMDA receptor–mediated component and amplitude of eEPSCs on heterotopic cells (MAM) but significantly decreased the late component and peak amplitude of eEPSCs in normotopic cells (Control). Our data demonstrate a functional alteration in the NMDA-mediated component of excitatory synaptic transmission in heterotopic cells and suggest that this alteration may be attributable, at least in part, to changes in composition and function of the NMDAR subunit. Changes in NMDA-receptor function may directly contribute to the hyperexcitability and cognitive deficits reported in animal models and patients with brain malformations.

Xenon Acts by Inhibition of Non–N -methyl-d-aspartate Receptor–mediated Glutamatergic Neurotransmission in Caenorhabditis elegans 

2005 ◽  
Vol 103 (3) ◽  
pp. 508-513 ◽  
Author(s):  
Peter Nagele ◽  
Laura B. Metz ◽  
C Michael Crowder
Keyword(s):  
Nitrous Oxide ◽  
Caenorhabditis Elegans ◽  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Glutamatergic Transmission ◽  
Wild Type ◽  
C Elegans ◽  
Aspartate Receptor ◽  
Nmda Glutamate Receptor ◽  
Response Transformation

Background Electrophysiologic experiments in rodents have found that nitrous oxide and xenon inhibit N-methyl-D-aspartate (NMDA)-type glutamate receptors. These findings led to the hypothesis that xenon and nitrous oxide along with ketamine form a class of anesthetics with the identical mechanism, NMDA receptor antagonism. Here, the authors ask in Caenorhabditis elegans whether xenon, like nitrous oxide, acts by a NMDA receptor-mediated mechanism. Methods Xenon:oxygen mixtures were delivered into sealed chambers until the desired concentration was achieved. The effects of xenon on various behaviors were measured on wild-type and mutant C. elegans strains. Results With an EC50 of 15-20 vol% depending on behavioral endpoint, xenon altered C. elegans locomotion in a manner indistinguishable from that of mutants in glutamatergic transmission. Xenon reduced the frequency and duration of backward locomotion without altering its speed or other behaviors tested. Mutation of glr-1, encoding a non-NMDA glutamate receptor subunit, abolished the behavioral effects of xenon; however, mutation of nmr-1, which encodes the pore-forming subunit of an NMDA glutamate receptor previously shown to be required for nitrous oxide action, did not significantly alter xenon response. Transformation of the glr-1 mutant with the wild-type glr-1 gene partially restored xenon sensitivity, confirming that glr-1 was necessary for the full action of xenon. Conclusions Xenon acts in C. elegans to alter locomotion through a mechanism requiring the non-NMDA glutamate receptor encoded by glr-1. Unlike for the action of nitrous oxide in C. elegans, the NMDA receptor encoded by nmr-1 is not essential for sensitivity to xenon.

scholarly journals STAT3 Suppresses The AMPKα-ULK1-Dependent Induction of Autophagy In Glioblastoma Cells

2021 ◽  
Author(s):  
Sujoy Bhattacharya ◽  
Jinggang Yin ◽  
Chuan He Yang ◽  
Yinan Wang ◽  
Michelle Sims ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tyrosine Phosphorylation ◽  
Autophagic Flux ◽  
Wild Type ◽  
Autophagy Flux ◽  
Stat3 Phosphorylation ◽  
Oncogenic Driver ◽  
Transcription 3 ◽  
Autophagy Inhibition ◽  
Stimulation Of

Abstract Despite advances in molecular characterization, glioblastoma (GBM) remains the most lethal type of brain tumor with high mortality rates in both pediatric and adult patients. The signal transducer and activator of transcription 3 (STAT3), is an important oncogenic driver of GBM. Although STAT3 reportedly plays a role in autophagy of some cells, its role in cancer cell autophagy remains unclear. In this study, we found STAT3 phosphorylation on Y705 and S727 residues, acetylation on K685, and tri-methylation on K180 was constitutive in GBM cell lines. Tyrosine phosphorylation of STAT3 in MT330 GBM cells suppresses autophagy, whereas knockout (KO) of STAT3 increases ULK1 gene expression, increases TSC2-AMPKa-ULK1 signaling and Prom1/CD133 expression, decreases p62 gene expression and accumulation, and increases lysosomal Cathepsin D processing, leading to the stimulation of autophagic flux. Rescue of STAT3-KO cells by the enforced expression of wild-type (WT) STAT3 reverses these pathways and inhibits autophagic flux. Conversely, expression of Y705F-STAT3 and S727A-STAT3 mutants in STAT3-KO cells did not suppress autophagy. Inhibition of ULK1 activity (by MRT68921) or its expression (by siRNA) in STAT3-KO cells inhibits autophagy flux and sensitizes cells to apoptosis. Taken together, our findings suggest that both STAT3 serine and tyrosine phosphorylation play critical roles in STAT3-dependent autophagy in GBM and the potential of targeting this pathway to treat GBM.

Enhanced tyrosine phosphorylation of the NMDA receptor subunit 2B and abnormal emotional response in Fyn-transgenic mice

1998 ◽  
Vol 31 ◽  
pp. S122 ◽  
Author(s):  
Nobuhiko Kojima ◽  
Oliver Stork ◽  
Hidetoshi Ishibashi ◽  
Simone Stork ◽  
Kunihiko Obata
Keyword(s):  
Nmda Receptor ◽  
Transgenic Mice ◽  
Tyrosine Phosphorylation ◽  
Emotional Response ◽  
Receptor Subunit ◽  
Nmda Receptor Subunit

Seizure activity results in increased tyrosine phosphorylation of the N-methyl-d-aspartate receptor in the hippocampus

2001 ◽  
Vol 95 (1-2) ◽  
pp. 36-47 ◽  
Author(s):  
Raffy C Moussa ◽  
Candace J Ikeda-Douglas ◽  
Varsha Thakur ◽  
Norton W Milgram ◽  
James W Gurd
Keyword(s):  
Tyrosine Phosphorylation ◽  
Seizure Activity ◽  
Aspartate Receptor

Review of synthetic approaches to dizocilpine

2020 ◽  
Vol 24 ◽  
Author(s):  
Jan Konecny ◽  
Eva Mezeiova ◽  
Ondrej Soukup ◽  
Jan Korabecny
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Neuronal Plasticity ◽  
Nmda Receptor Antagonist ◽  
Human Medicine ◽  
Ionotropic Glutamate Receptors ◽  
Nmda Receptor Antagonists ◽  
Nmda Antagonists ◽  
The Family ◽  
Synthetic Approaches

Abstract:: N-Methyl-D-aspartate (NMDA) receptors together with AMPA and kainite receptors belongs to the family of ionotropic glutamate receptors. NMDA receptors plays a crucial role in neuronal plasticity and cognitive functions. Overactivation of those receptors leads to glutamate induced excitotoxicity, which could be suppressed by NMDA antagonists. Dizocilpine was firstly reported in 1982 as a NMDA receptor antagonist with anticonvulsive properties, but due to serious side effects like neuronal vacuolization, its use in human medicine is restricted. However, dizocilpine is still used as validated tool to induce the symptoms of schizophrenia in animal models and also as a standart for comparative purposes to newly developed NMDA receptor antagonists. For this reason, synthesis of dizocilpine and specially its more active enantiomer (+)-dizocilpine is still relevant. In this review we bring a collection of various synthetic approaches leading to dizocilpine and its analogues.

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