Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats

An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca2+ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca2+ levels (NMDA-ΔCa2+) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa2+ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa2+ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca2+ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca2+ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa2+ signaling during HF are discussed.

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NMDA Receptor Activation by Spontaneous Glutamatergic Neurotransmission

Journal of Neurophysiology ◽

10.1152/jn.90754.2008 ◽

2009 ◽

Vol 101 (5) ◽

pp. 2290-2296 ◽

Cited By ~ 37

Author(s):

Felipe Espinosa ◽

Ege T. Kavalali

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Ampa Receptor ◽

Cortical Neurons ◽

Glutamate Release ◽

Receptor Activation ◽

Receptor Activity ◽

Resting Membrane Potential ◽

Nmda Current ◽

Nmda Receptor Activation

Under physiological conditions N-methyl-d-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg2+. Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately −67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises ∼20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately −50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.

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Integrated Regulation of Signal Coding and Plasticity by NMDA Receptors at a Central Synapse

Neural Plasticity ◽

10.1155/np.1998.8 ◽

1998 ◽

Vol 6 (3) ◽

pp. 8-16 ◽

Cited By ~ 7

Author(s):

Egidio D'Angelo ◽

Paola Rossi

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Membrane Depolarization ◽

Current Increase ◽

Nmda Current ◽

Signal Coding ◽

Spike Firing

The role of NMDA and non-NMDA glutamate receptors in long-term potentiation has been intensely investigated, yet recent evidence on the dynamics of synaptic depolarization suggests that the original view should be extended. NMDA receptor-mediated currents, apart from theirCa2+permeability, show a marked voltage dependence, consisting of current increase and slowdown during membrane depolarization. During highfrequency synaptic transmission, NMDA current increase and slowdown are primed by non-NMDA receptor-dependent depolarization and proceed regeneratively. Thus, NMDA receptors make a decisive contribution to membrane depolarization and spike-firing. From the data obtained at the mossy fiber- granule cell synapse of the cerebellum, we propose that the electrogenic role of NMDA receptors is functional to LTP induction. Moreover, during LTP, both NMDA and non- NMDA receptor currents are potentiated, thus establishing a feed-forward mechanism that ultimately enhances spike firing. Thus, NMDA receptors exert an integrated control on signal coding and plasticity. This mechanism may have important implications for information processing at the cerebellar mossy fibergranule cell relay.

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Thiopental Inhibits Increases in [Ca2+]iInduced by Membrane Depolarization, NMDA Receptor Activation, and Ischemia in Rat Hippocampal and Cortical Slices

Anesthesiology ◽

10.1097/00000542-199808000-00023 ◽

1998 ◽

Vol 89 (2) ◽

pp. 456-466 ◽

Cited By ~ 25

Author(s):

Ren-Zhi Zhan ◽

Naoshi Fujiwara ◽

Hiroshi Endoh ◽

Tomohiro Yamakura ◽

Kiichiro Taga ◽

...

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Hippocampal Slices ◽

Receptor Activation ◽

Membrane Depolarization ◽

In Vitro Ischemia ◽

High K ◽

Nmda Receptor Activation ◽

Cortical Slices

Background This study examined the effects of thiopental on intracellular calcium ([Ca2+]i) changes induced by membrane depolarization, N-methyl-D-aspartate (NMDA) receptor activation, and ischemia. Methods Experiments were performed in brain slices prepared from Wistar rats. [Ca2+]i measurements were taken on the CA1 pyramidal cell layer of the hippocampus or layers II to III of the somatosensory cortex using the fura-2 fluorescence technique. Membrane depolarization and NMDA receptor activation were induced by exposing slices to 60 mM K+ and 100 microM NMDA, respectively. In vitro ischemia was induced by superfusing slices with glucose-free Krebs solution equilibrated with 95% nitrogen and 5% carbon dioxide. Thiopental was applied 5 min before application of high K+ and NMDA, or before in vitro ischemia. Results Ischemia for 15 min produced a characteristic [Ca2+]i increase in both hippocampal and cortical slices. Thiopental prolonged the latency to the appearance of the [Ca2+]i plateau and reduced the magnitudes of increase in [Ca2+]i 8, 10, and 15 min after the onset of ischemia. Thiopental also suppressed the high K+- and NMDA-induced [Ca2+]i increases. The NMDA-induced [Ca2+]i increases were attenuated to a greater extent in cortical slices than were those in hippocampal slices. The inhibition of thiopental on the 200-microM NMDA-mediated [Ca2+]i response was confirmed in cultured cortical neurons. Conclusions The results indicate that thiopental attenuates ischemia-induced [Ca2+]i increases in the hippocampus and cortex in vitro, probably because of its inhibition of both voltage-gated calcium channels and NMDA receptors. The regionally different inhibition of thiopental on NMDA receptors may relate to its region-specific action against ischemia.

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NMDA and AMPA Receptors Contribute to the Nicotinic Cholinergic Excitation of CA1 Interneurons in the Rat Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00214.2003 ◽

2003 ◽

Vol 90 (3) ◽

pp. 1613-1625 ◽

Cited By ~ 37

Author(s):

Manickavasagom Alkondon ◽

Edna F.R. Pereira ◽

Edson X. Albuquerque

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Ampa Receptors ◽

Action Potentials ◽

Receptor Activation ◽

Membrane Potentials ◽

Glutamatergic Neurons ◽

Nicotinic Agonists ◽

Nmda Current ◽

Nicotinic Agonist

In the hippocampus, glutamatergic inputs to pyramidal neurons and interneurons are modulated by α7* and α3β4* nicotinic acetylcholine receptors (nAChRs), respectively, present in glutamatergic neurons. This study examines how nicotinic AMPA, and NMDA receptor nAChR activities are integrated to regulate the excitability of CA1 stratum radiatum (SR) interneurons in rat hippocampal slices. At resting membrane potentials and in the presence of extracellular Mg2+ (1 mM), nicotinic agonists triggered in SR interneurons excitatory postsynaptic currents (EPSCs) that had two components: one mediated by AMPA receptors, and the other by NMDA receptors. As previously shown, nicotinic agonist–triggered EPSCs resulted from glutamate released by activation of α3β4* nAChRs in glutamatergic neurons/fibers synapsing directly onto the neurons under study. The finding that CNQX caused more inhibition of nicotinic agonist–triggered EPSCs than expected from the blockade of postsynaptic AMPA receptors indicated that this nicotinic response also depended on the AMPA receptor activity in the glutamatergic neurons synapsing onto the interneuron under study. Nicotinic agonists always triggered action potentials in CA1 SR interneurons. In most interneurons, these action potentials resulted from activation of somatodendritic AMPA receptors and α7* nAChRs. In interneurons expressing somatodendritic α4β2* nAChRs, activation of these receptors caused sufficient membrane depolarization to remove the Mg2+-induced block of somatodendritic NMDA receptors; in these neurons, nicotinic agonist–triggered action potentials were partially dependent on NMDA receptor activation. Removing extracellular Mg2+ or clamping the neuron at positive membrane potentials revealed the existence of a tonic NMDA current in SR interneurons that was unaffected by nAChR activation or inhibition. Thus integration of the activities of nAChRs, NMDA, and AMPA receptors in different compartments of CA1 neurons contributes to the excitability of CA1 SR interneurons.

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Dynorphin A Elicits an Increase in Intracellular Calcium in Cultured Neurons Via a Non-Opioid, Non-NMDA Mechanism

Journal of Neurophysiology ◽

10.1152/jn.2000.83.5.2610 ◽

2000 ◽

Vol 83 (5) ◽

pp. 2610-2615 ◽

Cited By ~ 36

Author(s):

Qingbo Tang ◽

Ronald M. Lynch ◽

Frank Porreca ◽

Josephine Lai

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Intracellular Calcium ◽

Cortical Neurons ◽

Excitatory Amino Acid ◽

Receptor Activation ◽

Dependent Manner ◽

Dynorphin A ◽

Excitatory Effect

The opioid peptide dynorphin A is known to elicit a number of pathological effects that may result from neuronal excitotoxicity. An up-regulation of this peptide has also been causally related to the dysesthesia associated with inflammation and nerve injury. These effects of dynorphin A are not mediated through opioid receptor activation but can be effectively blocked by pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists, thus implicating the excitatory amino acid system as a mediator of the actions of dynorphin A and/or its fragments. A direct interaction between dynorphin A and the NMDA receptors has been well established; however the physiological relevance of this interaction remains equivocal. This study examined whether dynorphin A elicits a neuronal excitatory effect that may underlie its activation of the NMDA receptors. Calcium imaging of individual cultured cortical neurons showed that the nonopioid peptide dynorphin A(2-17) induced a time- and dose-dependent increase in intracellular calcium. This excitatory effect of dynorphin A(2-17) was insensitive to (+)-5-methyl-10,11-dihydro-5 H-dibenzo[ a,d]-cyclohepten-5,10-imine (MK-801) pretreatment in NMDA-responsive cells. Thus dynorphin A stimulates neuronal cells via a nonopioid, non-NMDA mechanism. This excitatory action of dynorphin A could modulate NMDA receptor activity in vivo by enhancing excitatory neurotransmitter release or by potentiating NMDA receptor function in a calcium-dependent manner. Further characterization of this novel site of action of dynorphin A may provide new insight into the underlying mechanisms of dynorphin excitotoxicity and its pathological role in neuropathy.

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NMDA receptors mediate peripheral chemoreceptor afferent input in the conscious rat

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.3.853 ◽

1998 ◽

Vol 84 (3) ◽

pp. 853-861 ◽

Cited By ~ 100

Author(s):

Patricia J. Ohtake ◽

José E. Torres ◽

Yair M. Gozal ◽

Gavin R. Graff ◽

David Gozal

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Receptor Activation ◽

Sodium Cyanide ◽

Respiratory Drive ◽

Peripheral Chemoreceptor ◽

Cardiorespiratory Control ◽

Mk 801 ◽

Ventilatory Responses ◽

Before And After

N-methyl-d-aspartate (NMDA) glutamate receptors mediate critical components of cardiorespiratory control in anesthetized animals. The role of NMDA receptors in the ventilatory responses to peripheral and central chemoreceptor stimulation was investigated in conscious, freely behaving rats. Minute ventilation (V˙e) responses to 10% O2, 5% CO2, and increasing intravenous doses of sodium cyanide were measured in intact rats before and after intravenous administration of the NMDA receptor antagonist MK-801 (3 mg/kg). After MK-801, eupcapnic tidal volume (Vt) decreased while frequency increased, resulting in a modest reduction inV˙e. Inspiratory time (Ti) decreased, whereas expiratory time remained unchanged. TheV˙e responses to hypercapnia were qualitatively similar in control and MK-801 conditions, with slight reductions in respiratory drive (Vt/Ti) after MK-801. In contrast, responses to hypoxia were markedly attenuated after MK-801 and were primarily due to reduced frequency changes, whereas Vt was unaffected. Sodium cyanide doses associated with significantV˙eincreases were 5 and 50 μg/kg before and after MK-801, respectively. Thus 1-log shift to the right of individual dose-response curves occurred with MK-801. Selective carotid body denervation reducedV˙e during hypoxia by 70%, and residual hypoxic ventilatory responses were abolished after MK-801. These findings suggest that, in conscious rats, carotid and other peripheral chemoreceptor-mediated hypoxic ventilatory responses are critically dependent on NMDA receptor activation and that NMDA receptor mechanisms are only modestly involved during hypercapnia.

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Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula

Science ◽

10.1126/science.aax1522 ◽

2019 ◽

Vol 366 (6462) ◽

pp. 250-254 ◽

Cited By ~ 9

Author(s):

Y. Otsu ◽

E. Darcq ◽

K. Pietrajtis ◽

F. Mátyás ◽

E. Schwartz ◽

...

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Glial Cells ◽

Neuronal Activity ◽

The Other ◽

Place Aversion ◽

Nmda Receptor Subunits ◽

Medial Habenula ◽

Aversion Conditioning ◽

Binding Subunit

The unconventional N-methyl-d-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.

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Spike Patterning by Ca2+-Dependent Regulation of a Muscarinic Cation Current in Entorhinal Cortex Layer II Neurons

Journal of Neurophysiology ◽

10.1152/jn.00036.2004 ◽

2004 ◽

Vol 92 (3) ◽

pp. 1644-1657 ◽

Cited By ~ 30

Author(s):

Jacopo Magistretti ◽

Li Ma ◽

Mark H. Shalinsky ◽

Wei Lin ◽

Ruby Klink ◽

...

Keyword(s):

Entorhinal Cortex ◽

Chelating Agents ◽

Receptor Activation ◽

Emergent Properties ◽

Firing Activity ◽

Cation Current ◽

Muscarinic Stimulation ◽

Intracellular Ca ◽

Positive And Negative Feedback ◽

Activity Dependent

In entorhinal cortex layer II neurons, muscarinic receptor activation promotes depolarization via activation of a nonspecific cation current ( INCM). Under muscarinic influence, these neurons also develop changes in excitability that result in activity-dependent induction of delayed firing and bursting activity. To identify the membrane processes underlying these phenomena, we examined whether INCM may undergo activity-dependent regulation. Our voltage-clamp experiments revealed that appropriate depolarizing protocols increased the basal level of inward current activated during muscarinic stimulation and suggested that this effect was due to INCM upregulation. In the presence of low buffering for intracellular Ca2+, this upregulation was transient, and its decay could be followed by a phase of INCM downregulation. Both up- and downregulation were elicited by depolarizing stimuli able to activate voltage-gated Ca2+ channels (VGCC); both were sensitive to increasing concentrations of intracellular Ca2+-chelating agents with downregulation being abolished at lower Ca2+-buffering capacities; both were reduced or suppressed by VGCC block or in the absence of extracellular Ca2+. These data indicate that relatively small increases in [Ca2+]i driven by firing activity can induce upregulation of a basal muscarinic depolarizing-current level, whereas more pronounced [Ca2+]i elevations can result in INCM downregulation. We propose that the interaction of activity-dependent positive and negative feedback mechanisms on INCM allows entorhinal cortex layer II neurons to exhibit emergent properties, such as delayed firing and enhanced or suppressed responses to repeated stimuli, that may be of importance in the memory functions of the temporal lobe and in the pathophysiology of epilepsy.

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The effect of varying stimulus intensity on NMDA-receptor activity in cat visual cortex

Journal of Neurophysiology ◽

10.1152/jn.1990.64.5.1413 ◽

1990 ◽

Vol 64 (5) ◽

pp. 1413-1428 ◽

Cited By ~ 117

Author(s):

K. Fox ◽

H. Sato ◽

N. Daw

Keyword(s):

Visual Cortex ◽

Nmda Receptor ◽

Nmda Receptors ◽

Receptor Activation ◽

Visual Response ◽

Background Luminance ◽

Stimulus Contrast ◽

Cat Visual Cortex ◽

Low Levels ◽

Nmda Receptor Activation

1. A study was made of the relative contribution of N-methyl-D-aspartate (NMDA) and non-NMDA receptors to the visual responses of cells in different layers of the cat visual cortex at different levels of excitatory drive (which was varied by altering the stimulus contrast). 2. Receptive fields were mapped for 121 cells in area 17 of cat cortex. Cells were characterized to determine the optimal visual stimulus, the brightness of which was then varied relative to background luminance to construct a contrast-response (C-R) curve for each cell. Curves were made during control conditions and during application of agonists (NMDA and quisqualate) and/or antagonists [(D)-2-amino-5-phosphonovaleric acid (D-APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)] to examine the excitatory amino acid components of the visual response. 3. Threshold responses were obtained with stimuli between 1/60 and 1.8 X background luminance. The cell response, measured by firing rate, was linearly related to stimulus contrast over 1-2 decades and saturated at higher contrasts. 4. Application of APV reduced the slope of the linear portion of the C-R curve for cells located in layers II and III (average reduction, 59% of control). APV did not decrease the threshold to stimulation. The "just suprathreshold" responses to stimulation were reduced by the same proportion as the saturation responses for individual cells. The principal effect was therefore to reduce the gain of the C-R curve in these layers. 5. Application of APV reduced the spontaneous activity of cells located in layers IV, V, and VI with little if any effect on the gain of the C-R curve. This suggests a tonic background level of NMDA-receptor activation in these layers, which is not directly related to the visual response. 6. Low levels of NMDA increased the gain of the C-R curve in layers II/III and V/VI. On the other hand, low levels of quisqualate increased the overall level of firing without affecting the gain of the C-R curve. NMDA did not increase the gain of the curve in layer IV. 7. These experiments show that visual stimuli that produce just suprathreshold responses activate NMDA receptors. The degree of activation is proportionally the same for small responses and large responses for an individual cell. Rather than finding a threshold for NMDA-receptor activation, a continuous range of NMDA-receptor influence was observed over the entire response range.(ABSTRACT TRUNCATED AT 250 WORDS)

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CCK-Induced Reduction of Food Intake and Hindbrain MAPK Signaling Are Mediated by NMDA Receptor Activation

Endocrinology ◽

10.1210/en.2012-1025 ◽

2012 ◽

Vol 153 (6) ◽

pp. 2633-2646 ◽

Cited By ~ 30

Author(s):

Carlos A. Campos ◽

Jason S. Wright ◽

Krzysztof Czaja ◽

Robert C. Ritter

Keyword(s):

Nmda Receptor ◽

Food Intake ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Fourth Ventricle ◽

Receptor Activation ◽

Nmda Receptor Antagonist ◽

Vagal Afferents ◽

Mapk Kinase ◽

Vagal Afferent

The dorsal vagal complex of the hindbrain, including the nucleus of the solitary tract (NTS), receives neural and humoral afferents that contribute to the process of satiation. The gut peptide, cholecystokinin (CCK), promotes satiation by activating gastrointestinal vagal afferents that synapse in the NTS. Previously, we demonstrated that hindbrain administration of N-methyl-d-aspartate (NMDA)-type glutamate receptor antagonists attenuate reduction of food intake after ip CCK-8 injection, indicating that these receptors play a necessary role in control of food intake by CCK. However, the signaling pathways through which hindbrain NMDA receptors contribute to CCK-induced reduction of food intake have not been investigated. Here we report CCK increases phospho-ERK1/2 in NTS neurons and in identified vagal afferent endings in the NTS. CCK-evoked phospho-ERK1/2 in the NTS was attenuated in rats pretreated with capsaicin and was abolished by systemic injection of a CCK1 receptor antagonist, indicating that phosphorylation of ERK1/2 occurs in and is mediated by gastrointestinal vagal afferents. Fourth ventricle injection of a competitive NMDA receptor antagonist, prevented CCK-induced phosphorylation of ERK1/2 in hindbrain neurons and in vagal afferent endings, as did direct inhibition of MAPK kinase. Finally, fourth ventricle administration of either a MAPK kinase inhibitor or NMDA receptor antagonist prevented the reduction of food intake by CCK. We conclude that activation of NMDA receptors in the hindbrain is necessary for CCK-induced ERK1/2 phosphorylation in the NTS and consequent reduction of food intake.

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