Probability of Transmitter Release at Neocortical Synapses at Different Temperatures

2004 ◽  
Vol 92 (1) ◽  
pp. 212-220 ◽  
Author(s):  
Maxim Volgushev ◽  
Igor Kudryashov ◽  
Marina Chistiakova ◽  
Mikhail Mukovski ◽  
Johannes Niesmann ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Nmda Receptor ◽  
Transmitter Release ◽  
Room Temperature ◽  
Time Course ◽  
Dynamic Properties ◽  
Variable Temperature ◽  
Pyramidal Cells ◽  
Mk 801 ◽  
Release Probability

The probability of transmitter release at synaptic terminals is one of the key characteristics of communication between nerve cells because it determines both the strength and dynamic properties of synaptic connections. To assess the distribution of the release probabilities at excitatory synapses on supragranular pyramidal cells in rat visual cortex, we have used the MK-801, a blocker of the open N-methyl-d-aspartate (NMDA) receptor-gated channels. With this method, the release probability can be calculated from the time course of the blockade of NMDA-receptor mediated postsynaptic currents in the presence of MK-801. At temperatures >32°C, the distribution of release probabilities covered the range from 0.05 to 0.43 [mean: 0.171 ± 0.012 (SE), n = 65], being skewed toward low values. When estimated at room temperature (22–25°C), the release probabilities were significantly lower (mean: 0.123 ± 0.009, n = 54), and almost the whole distribution was restricted to values <0.2. Furthermore, warming from room temperature to >32°C led to a pronounced overshooting increase of the release probability. Taken together, the results of the present study show that release probabilities at synapses formed onto layer 2/3 pyramidal cells in the visual cortex vary significantly, but values >0.3 are rare and the results obtained either at room or variable temperature differ significantly from those made under conditions of constant temperature in the physiological range.

Adaptation at Synaptic Connections to Layer 2/3 Pyramidal Cells in Rat Visual Cortex

2005 ◽  
Vol 94 (1) ◽  
pp. 363-376 ◽  
Author(s):  
Oliver Beck ◽  
Marina Chistiakova ◽  
Klaus Obermayer ◽  
Maxim Volgushev
Keyword(s):  
Visual Cortex ◽  
Dynamic Properties ◽  
Pyramidal Cells ◽  
Response Amplitude ◽  
Release Probability ◽  
Layer 2 ◽  
Synaptic Dynamics ◽  
Synaptic Parameters ◽  
Strong Adaptation ◽  
40 Hz

Neocortical synapses express differential dynamic properties. When activated at high frequencies, the amplitudes of the subsequent postsynaptic responses may increase or decrease, depending on the stimulation frequency and on the properties of that particular synapse. Changes in the synaptic dynamics can dramatically affect the communication between nerve cells. Motivated by this question, we studied dynamic properties at synapses to layer 2/3 pyramidal cells with intracellular recordings in slices of rat visual cortex. Synaptic responses were evoked by trains of test stimuli, which consisted of 10 pulses at different frequencies (5–40 Hz). Test stimulation was applied either without any adaptation (control) or 2 s after an adaptation stimulus, which consisted of 4 s stimulation of these same synapses at 10, 25, or 40 Hz. The synaptic parameters were then assessed from fitting the data with a model of synaptic dynamics. Our estimates of the synaptic parameters in control, without adaptation are broadly consistent with previous studies. Adaptation led to pronounced changes of synaptic transmission. After adaptation, the amplitude of the response to the first pulse in the test train decreased for several seconds and then recovered back to the control level with a time constant of 2–18 s. Analysis of the data with extended models, which include interaction between different pools of synaptic vesicles, suggests that the decrease of the response amplitude was due to a synergistic action of two factors, decrease of the release probability and depletion of the available transmitter. After a weak (10 Hz) adaptation, the decrease of the response amplitude was accompanied by and correlated with the decrease of the release probability. After a strong adaptation (25 or 40 Hz), the depletion of synaptic resources was the main cause for the reduced response amplitude. Adaptation also led to pronounced changes of the time constants of facilitation and recovery, however, these changes were not uniform in all synapses, and on the population level, the only consistent and significant effect was an acceleration of the recovery after a strong adaptation. Taken together, our results suggest, that apart from decreasing the amplitude of postsynaptic responses, adaptation may produce synapse-specific effects, which could result in a kind of re-distribution of activity within neural networks.

MK-801 does not prevent impaired cerebrovascular reactivity to CO2 during hypoglycemia in piglets

1993 ◽  
Vol 264 (6) ◽  
pp. H2124-H2130
Author(s):  
P. J. St Jacques ◽  
J. R. Kirsch ◽  
M. N. Diringer ◽  
R. J. Traystman
Keyword(s):  
Nmda Receptor ◽  
Time Course ◽  
Nmda Receptor Antagonist ◽  
Cerebrovascular Reactivity ◽  
Co2 Reactivity ◽  
Resistance Change ◽  
Mk 801 ◽  
Cerebrovascular Resistance ◽  
Cerebrovascular Co2 Reactivity ◽  
Made In

We tested the hypothesis that severe insulin-induced hypoglycemia would depress cerebrovascular reactivity to CO2 via a mechanism that could be prevented by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 in infant piglets. Cerebral blood flow (CBF) was measured (microspheres) in 2- to 3-wk-old pentobarbital-anesthetized piglets during hypocapnia, normocapnia, and hypercapnia. Repeat CBF measurements were made either 1 (n = 5) or 2 h (n = 6) after insulin (200 U/kg iv) to elicit the time course of altered reactivity to CO2. Repeat CBF measurements were made in a third group (n = 5) 2 h after treatment with insulin and MK-801 (1.5 mg/kg iv bolus, 0.15 mg.kg-1.h-1 iv infusion) to determine whether any alteration in reactivity to CO2 was due to a mechanism involving the NMDA receptor. Cerebrovascular resistance and cerebral O2 consumption (CMRO2) were calculated with each measurement of CBF. Cerebrovascular response to CO2 (change in cerebrovascular resistance/change in arterial CO2 tension) was ablated in the group of piglets exposed to 1 or 2 h of hypoglycemia (preinsulin 1-h group, 0.038 +/- 0.007; preinsulin 2-h group, 0.023 +/- 0.004 mmHg.ml-1.min.100 g.mmHg CO2(-1)). Treatment with MK-801 did not alter normoglycemic CO2 reactivity (preinsulin, 0.032 +/- 0.005 mmHg.ml-1.min.100 g.mmHg CO2(-1)) and did not prevent ablation of cerebrovascular CO2 reactivity during hypoglycemia. CMRO2 was not affected by hypoglycemia in any group.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Regionally Selective Effects of NMDA Receptor Antagonists against Ischemic Brain Damage in the Gerbil

1991 ◽  
Vol 11 (4) ◽  
pp. 600-610 ◽  
Author(s):  
Michael A. Warner ◽  
Kenneth H. Neill ◽  
J. Victor Nadler ◽  
Barbara J. Crain
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Cells ◽  
Carotid Occlusion ◽  
Neuroprotective Activity ◽  
Ischemic Damage ◽  
Nmda Receptor Antagonists ◽  
Receptor Antagonists ◽  
Mk 801 ◽  
Ca1 Pyramidal Cells ◽  
Cgs 19755

This study compared the ability of three N-methyl-D-aspartate (NMDA) receptor antagonists to prevent neuronal degeneration in an animal model of global cerebral ischemia. The model employed is characterized by damage to the striatum, hippocampus, and neocortex. Antagonists were administered to gerbils either before or after a 5-min bilateral carotid occlusion. The intraischemic rectal temperature was either maintained at 36–37°C or allowed to fall passively to 28–32°C. Antagonists and doses tested were 1 and 10 mg/kg of MK-801 (pre- or postischemia), 30 mg/kg of CGS 19755 preischemia, four 25 mg/kg doses of CGS 19755 administered between 0.5 and 6.5 h postischemia, and 40 mg/kg of MDL 27,266 (pre- or postischemia). All three NMDA receptor antagonists exhibited some degree of neuroprotective activity when the carotid occlusion was performed under normothermic conditions. Most of the treatments with antagonist markedly reduced striatal damage. CA1 hippocampal and neocortical pyramidal cells were spared by only three of the treatments, however, and the extent of neuroprotection varied widely from case to case. Toxic doses of antagonist were required to protect CA1 pyramidal cells from ischemic damage. Ischemic damage to hippocampal areas CA2–CA3a and CA4 appeared to be resistant to all of these treatments. Most CA1 pyramidal cells that were protected from degeneration by an NMDA receptor antagonist were histologically abnormal. The neuroprotective effects of MK-801 and intraischemic hypothermia appeared to be additive. MK-801 (10 mg/kg) consistently reduced the postischemic brain temperature, but only the magnitude of hypothermia produced soon after reperfusion correlated with its neuroprotective action. These results suggest that NMDA receptor antagonists are relatively poor neuroprotective agents against a moderately severe ischemic insult.

scholarly journals Regional Neuroprotective Effects of the NMDA Receptor Antagonist MK-801 (Dizocilpine) in Hypoglycemic Brain Damage

1990 ◽  
Vol 10 (2) ◽  
pp. 270-276 ◽  
Author(s):  
M. P. Papagapiou ◽  
R. N. Auer
Keyword(s):  
Nmda Receptor ◽  
Brain Temperature ◽  
Neuroprotective Effect ◽  
Pyramidal Cells ◽  
Receptor Activation ◽  
Brain Regions ◽  
Current Evidence ◽  
Neuroprotective Effects ◽  
Neuronal Necrosis ◽  
Mk 801

Current evidence points to an important role of N-methyl-d-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 {dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5 H-di[ a,d]cyclohepten-5,10-imine} is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood–brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5–5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5–2.0 m M) at the stage of δ-wave (1–4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of δ-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.

scholarly journals In vivo glucose metabolism and glutamate levels in mGluR5 knockout mice: a multimodal neuroimaging study using [18F]FDG microPET and MRS

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yo-Han Joo ◽  
Yun-Kwan Kim ◽  
In-Gyu Choi ◽  
Hyeon-Jin Kim ◽  
Young-Don Son ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Glucose Metabolism ◽  
Cerebral Glucose Metabolism ◽  
Functional Coupling ◽  
Resonance Spectroscopy ◽  
Acute Administration ◽  
Multimodal Neuroimaging ◽  
Mk 801 ◽  
Genetic Ablation ◽  
Neuroimaging Study

Abstract Background Perturbed functional coupling between the metabotropic glutamate receptor-5 (mGluR5) and N-methyl-d-aspartate (NMDA) receptor-mediated excitatory glutamatergic neurotransmission may contribute to the pathophysiology of psychiatric disorders such as schizophrenia. We aimed to establish the functional interaction between mGluR5 and NMDA receptors in brain of mice with genetic ablation of the mGluR5. Methods We first measured the brain glutamate levels with magnetic resonance spectroscopy (MRS) in mGluR5 knockout (KO) and wild-type (WT) mice. Then, we assessed brain glucose metabolism with [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography before and after the acute administration of an NMDA antagonist, MK-801 (0.5 mg/kg), in the same mGluR5 KO and WT mice. Results Between-group comparisons showed no significant differences in [18F]FDG standardized uptake values (SUVs) in brain of mGluR5 KO and WT mice at baseline, but widespread reductions in mGluR5 KO mice compared to WT mice after MK-801 administration (p < 0.05). The baseline glutamate levels did not differ significantly between the two groups. However, there were significant negative correlations between baseline prefrontal glutamate levels and regional [18F]FDG SUVs in mGluR5 KO mice (p < 0.05), but no such correlations in WT mice. Fisher’s Z-transformation analysis revealed significant between-group differences in these correlations (p < 0.05). Conclusions This is the first multimodal neuroimaging study in mGluR5 KO mice and the first report on the association between cerebral glucose metabolism and glutamate levels in living rodents. The results indicate that mGluR5 KO mice respond to NMDA antagonism with reduced cerebral glucose metabolism, suggesting that mGluR5 transmission normally moderates the net effects of NMDA receptor antagonism on neuronal activity. The negative correlation between glutamate levels and glucose metabolism in mGluR5 KO mice at baseline may suggest an unmasking of an inhibitory component of the glutamatergic regulation of neuronal energy metabolism.

scholarly journals Ketamine Produces a Long-Lasting Enhancement of CA1 Neuron Excitability

2021 ◽  
Vol 22 (15) ◽  
pp. 8091
Author(s):  
Grace Jang ◽  
M. Bruce MacIver
Keyword(s):  
Nmda Receptor ◽  
Potassium Channel ◽  
Receptor Antagonist ◽  
Hippocampal Slices ◽  
Nmda Receptor Antagonist ◽  
Channel Block ◽  
Mk 801 ◽  
Ca1 Region ◽  
Excitatory Transmission ◽  
Ketamine Anesthesia

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine’s actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.

scholarly journals Pitfalls of NMDA Receptor Modulation by Neuroactive Steroids. The Effect of Positive and Negative Modulation of NMDA Receptors in an Animal Model of Schizophrenia

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1026
Author(s):  
Kristina Holubova ◽  
Marketa Chvojkova ◽  
Barbora Hrcka Krausova ◽  
Vojtech Vyklicky ◽  
Eva Kudova ◽  
...  
Keyword(s):  
Animal Model ◽  
Nmda Receptor ◽  
Neuroactive Steroids ◽  
Stress Exposure ◽  
Mk 801 ◽  
Receptor Modulator ◽  
Receptor Modulation ◽  
Antipsychotic Effect ◽  
Response To Stress ◽  
Systemic Application

Evidence from clinical and preclinical studies implicates dysfunction of N-methyl-D-aspartate receptors (NMDARs) in schizophrenia progression and symptoms. We investigated the antipsychotic effect of two neuroactive steroids in an animal model of schizophrenia induced by systemic application of MK-801. The neuroactive steroids differ in their mechanism of action at NMDARs. MS-249 is positive, while PA-Glu is a negative allosteric NMDAR modulator. We hypothesized that the positive NMDA receptor modulator would attenuate deficits caused by MK-801 co-application more effectively than PA-Glu. The rats were tested in a battery of tests assessing spontaneous locomotion, anxiety and cognition. Contrary to our expectations, PA-Glu exhibited a superior antipsychotic effect to MS-249. The performance of MS-249-treated rats in cognitive tests differed depending on the level of stress the rats were exposed to during test sessions. In particular, with the increasing severity of stress exposure, the performance of animals worsened. Our results demonstrate that enhancement of NMDAR function may result in unspecific behavioral responses. Positive NMDAR modulation can influence other neurobiological processes besides memory formation, such as anxiety and response to stress.

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