A network model of the modulation of gamma oscillations by NMDA receptors in cerebral cortex

Mapping Intimacies ◽

10.1101/2021.12.21.473671 ◽

2021 ◽

Author(s):

Eduarda Susin ◽

Alain Destexhe

Keyword(s):

Cerebral Cortex ◽

Nmda Receptors ◽

Computational Models ◽

Gamma Oscillations ◽

Inhibitory Interneurons ◽

Nmda Receptor Antagonists ◽

Nmda Antagonists ◽

Gamma Power ◽

Underlying Mechanisms ◽

External Stimuli

Psychotic drugs such as ketamine induce symptoms close to schizophrenia, and stimulates the production of gamma oscillations, as also seen in patients, but the underlying mechanisms are still unclear. Here, we have used computational models of cortical networks generating gamma oscillations, and have integrated the action of drugs such as ketamine to partially block n-methyl-d-Aspartate (NMDA) receptors. The model can reproduce the modulation of gamma oscillations by NMDA-receptor antagonists, assuming that antagonists affect NMDA receptors predominantly on inhibitory interneurons. We next used the model to compare the responsiveness of the network to external stimuli, and found that when NMDA channnels are blocked an increase of Gamma power is observed altogether with an increase of network responsiveness. However, this responsiveness increase applies not only to gamma states, but also to synchronous states with no apparent gamma. We conclude that NMDA antagonists induce increased excitability state, which may or may not produce gamma oscillations, but the response to external inputs is exacerbated, which may explain phenomena such as altered perception or hallucinations.

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Integration, coincidence detection and resonance in networks of spiking neurons expressing Gamma oscillations and asynchronous states

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009416 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009416

Author(s):

Eduarda Susin ◽

Alain Destexhe

Keyword(s):

Cerebral Cortex ◽

Pyramidal Neurons ◽

Network Models ◽

Cell Types ◽

Gamma Oscillations ◽

Coincidence Detection ◽

Biophysical Models ◽

Firing Mode ◽

Different Cell Types ◽

External Stimuli

Gamma oscillations are widely seen in the awake and sleeping cerebral cortex, but the exact role of these oscillations is still debated. Here, we used biophysical models to examine how Gamma oscillations may participate to the processing of afferent stimuli. We constructed conductance-based network models of Gamma oscillations, based on different cell types found in cerebral cortex. The models were adjusted to extracellular unit recordings in humans, where Gamma oscillations always coexist with the asynchronous firing mode. We considered three different mechanisms to generate Gamma, first a mechanism based on the interaction between pyramidal neurons and interneurons (PING), second a mechanism in which Gamma is generated by interneuron networks (ING) and third, a mechanism which relies on Gamma oscillations generated by pacemaker chattering neurons (CHING). We find that all three mechanisms generate features consistent with human recordings, but that the ING mechanism is most consistent with the firing rate change inside Gamma bursts seen in the human data. We next evaluated the responsiveness and resonant properties of these networks, contrasting Gamma oscillations with the asynchronous mode. We find that for both slowly-varying stimuli and precisely-timed stimuli, the responsiveness is generally lower during Gamma compared to asynchronous states, while resonant properties are similar around the Gamma band. We could not find conditions where Gamma oscillations were more responsive. We therefore predict that asynchronous states provide the highest responsiveness to external stimuli, while Gamma oscillations tend to overall diminish responsiveness.

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Integration, coincidence detection and resonance in networks of spiking neurons expressing gamma oscillations and asynchronous states

10.1101/2021.05.03.442436 ◽

2021 ◽

Author(s):

Eduarda Susin ◽

Alain Destexhe

Keyword(s):

Cerebral Cortex ◽

Pyramidal Neurons ◽

Network Models ◽

Cell Types ◽

Gamma Oscillations ◽

Coincidence Detection ◽

Biophysical Models ◽

Firing Mode ◽

Different Cell Types ◽

External Stimuli

Gamma oscillations are widely seen in the awake and sleeping cerebral cortex, but the exact role of these oscillations is still debated. Here, we used biophysical models to examine how gamma oscillations may participate to the processing of afferent stimuli. We constructed conductance-based network models of gamma oscillations, based on different cell types found in cerebral cortex. The models were adjusted to extracellular unit recordings in humans, where gamma oscillations always coexist with the asynchronous firing mode. We considered three different mechanisms to generate gamma, first a mechanism based on the interaction between pyramidal neurons and interneurons (PING), second a mechanism in which gamma is generated in interneuron networks (ING) and third, a mechanism which relies on gamma oscillations generated by pacemaker Chattering neurons (CHING). We find that all three mechanisms generate features consistent with human recordings, but that the ING mechanism is most consistent with the firing rate change inside Gamma bursts seen in the human data. We next evaluated the responsiveness and resonant properties of these networks, contrasting gamma oscillations with the asynchronous mode. We find that for both slowly-varying stimuli and precisely-timed stimuli, the responsiveness is generally lower during Gamma compared to asynchronous states, while resonant properties are similar around the Gamma band. We could not find conditions where Gamma oscillations were more responsive. We therefore predict that asynchronous states provide the highest responsiveness to external stimuli, while Gamma oscillations tend to overall diminish responsiveness.

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Review of synthetic approaches to dizocilpine

Current Organic Chemistry ◽

10.2174/1385272824999201230205835 ◽

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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Hippocampal pattern completion is linked to gamma power increases and alpha power decreases during recollection

eLife ◽

10.7554/elife.17397 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 44

Author(s):

Bernhard P Staresina ◽

Sebastian Michelmann ◽

Mathilde Bonnefond ◽

Ole Jensen ◽

Nikolai Axmacher ◽

...

Keyword(s):

Computational Models ◽

Memory Task ◽

Alpha Power ◽

Single Shot ◽

Pattern Completion ◽

Time Frequency ◽

Oscillatory Dynamics ◽

Gamma Power ◽

Human Participants ◽

Underlying Mechanisms

How do we retrieve vivid memories upon encountering a simple cue? Computational models suggest that this feat is accomplished by pattern completion processes involving the hippocampus. However, empirical evidence for hippocampal pattern completion and its underlying mechanisms has remained elusive. Here, we recorded direct intracranial EEG as human participants performed an associative memory task. For each study (encoding) and test (retrieval) event, we derived time-frequency resolved representational patterns in the hippocampus and compared the extent of pattern reinstatement for different mnemonic outcomes. Results show that successful associative recognition (AR) yields enhanced event-specific reinstatement of encoding patterns compared to non-associative item recognition (IR). Moreover, we found that gamma power (50–90 Hz) increases – in conjunction with alpha power (8–12 Hz) decreases not only distinguish AR from IR, but also correlate with the level of hippocampal reinstatement. These results link single-shot hippocampal pattern completion to episodic recollection and reveal how oscillatory dynamics in the gamma and alpha bands orchestrate these mnemonic processes.

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Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2011 ◽

2011 ◽

Vol 301 (2) ◽

pp. R448-R455 ◽

Cited By ~ 25

Author(s):

Jason Wright ◽

Carlos Campos ◽

Thiebaut Herzog ◽

Mihai Covasa ◽

Krzysztof Czaja ◽

...

Keyword(s):

Nmda Receptor ◽

Food Intake ◽

Nmda Receptors ◽

Receptor Antagonist ◽

Fourth Ventricle ◽

Nmda Receptor Antagonist ◽

Behavioral Pattern ◽

Vagal Afferents ◽

Nmda Receptor Antagonists ◽

The Brain

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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Frontal eye field microstimulation induces task-dependent gamma oscillations in the lateral intraparietal area

Journal of Neurophysiology ◽

10.1152/jn.00323.2012 ◽

2012 ◽

Vol 108 (5) ◽

pp. 1392-1402 ◽

Cited By ~ 15

Author(s):

Elsie Premereur ◽

Wim Vanduffel ◽

Pieter R. Roelfsema ◽

Peter Janssen

Keyword(s):

Spatial Attention ◽

Field Potential ◽

Gamma Oscillations ◽

Oculomotor Control ◽

Saccade Target ◽

Frontal Eye Field ◽

Alpha Power ◽

Lateral Intraparietal Area ◽

Electrical Microstimulation ◽

Gamma Power

Macaque frontal eye fields (FEF) and the lateral intraparietal area (LIP) are high-level oculomotor control centers that have been implicated in the allocation of spatial attention. Electrical microstimulation of macaque FEF elicits functional magnetic resonance imaging (fMRI) activations in area LIP, but no study has yet investigated the effect of FEF microstimulation on LIP at the single-cell or local field potential (LFP) level. We recorded spiking and LFP activity in area LIP during weak, subthreshold microstimulation of the FEF in a delayed-saccade task. FEF microstimulation caused a highly time- and frequency-specific, task-dependent increase in gamma power in retinotopically corresponding sites in LIP: FEF microstimulation produced a significant increase in LIP gamma power when a saccade target appeared and remained present in the LIP receptive field (RF), whereas less specific increases in alpha power were evoked by FEF microstimulation for saccades directed away from the RF. Stimulating FEF with weak currents had no effect on LIP spike rates or on the gamma power during memory saccades or passive fixation. These results provide the first evidence for task-dependent modulations of LFPs in LIP caused by top-down stimulation of FEF. Since the allocation and disengagement of spatial attention in visual cortex have been associated with increases in gamma and alpha power, respectively, the effects of FEF microstimulation on LIP are consistent with the known effects of spatial attention.

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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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Excitatory Projection Neuron Subtypes Control the Distribution of Local Inhibitory Interneurons in the Cerebral Cortex

Neuron ◽

10.1016/j.neuron.2011.01.015 ◽

2011 ◽

Vol 69 (4) ◽

pp. 763-779 ◽

Cited By ~ 122

Author(s):

Simona Lodato ◽

Caroline Rouaux ◽

Kathleen B. Quast ◽

Chanati Jantrachotechatchawan ◽

Michèle Studer ◽

...

Keyword(s):

Cerebral Cortex ◽

Projection Neuron ◽

Inhibitory Interneurons ◽

Excitatory Projection

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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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