Involvement Of NMDA Receptors Research Articles

Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner

BackgroundDevelopment of synaptic activity is a key neuronal characteristic that relies largely on interactions between neurons and astrocytes. Although astrocytes have known roles in regulating synaptic function and malfunction, the use of human- or donor-specific astrocytes in disease models is still rare. Rodent astrocytes are routinely used to enhance neuronal activity in cell cultures, but less is known about how human astrocytes influence neuronal activity. MethodsWe established human induced pluripotent stem cell–derived neuron-astrocyte cocultures and studied their functional development on microelectrode array. We used cell lines from 5 neurotypical control individuals and 3 pairs of monozygotic twins discordant for schizophrenia. A method combining NGN2 overexpression and dual SMAD inhibition was used for neuronal differentiation. The neurons were cocultured with human induced pluripotent stem cell–derived astrocytes differentiated from 6-month-old astrospheres or rat astrocytes. ResultsWe found that the human induced pluripotent stem cell–derived cocultures developed complex network bursting activity similar to neuronal cocultures with rat astrocytes. However, the effect of NMDA receptors on neuronal network burst frequency (NBF) differed between cocultures containing human or rat astrocytes. By using cocultures derived from patients with schizophrenia and unaffected individuals, we found lowered NBF in the affected cells. We continued by demonstrating how astrocytes from an unaffected individual rescued the lowered NBF in the affected neurons by increasing NMDA receptor activity. ConclusionsOur results indicate that astrocytes participate in the regulation of neuronal NBF through a mechanism that involves NMDA receptors. These findings shed light on the importance of using human and donor-specific astrocytes in disease modeling.

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

Analysis of the Involvement of NMDA Receptors in Analgesia and Hypothermia Induced by the Activation of TRPV1 Ion Channels.

NMDA glutamate receptors play an important role in normal and pathophysiological nociception. At the periphery, they can interact with TRPV1 ion channels. The blockade of TRPV1 ion channels decreases NMDA-induced hyperalgesia, and NMDA receptor antagonists suppress the pain response to the TRPV1 agonist capsaicin. Since TRPV1 ion channels and NMDA receptors can functionally interact at the periphery, it would be interesting to investigate the possibility that they interact in the CNS. A single subcutaneous injection of 1 mg/kg of capsaicin was found to raise the thermal pain threshold in the tail flick test in mice, which reproduces the spinal flexion reflex, owing to the ability of capsaicin to cause long-term desensitization of nociceptors. Preventive administration of either noncompetitive NMDA receptor antagonists (high-affinity MK-801 20 μg/kg and 0.5 mg/kg subcutaneously; low-affinity hemantane 40 mg/kg intraperitoneally) or the selective TRPV1 antagonist BCTC (20 mg/kg intraperitoneally) inhibit the capsaicin-induced increase in the pain threshold. Capsaicin (1 mg/kg, subcutaneous injection) induces transient hypothermia in mice, which is brought about by hypothalamus-triggered vegetative reactions. This effect is prevented by BCTC but not by the noncompetitive NMDA receptor antagonists.

NMDA receptor-mediated modulation on glutamine synthetase and glial glutamate transporter GLT-1 is involved in the antidepressant-like and neuroprotective effects of guanosine

Guanosine has been reported to elicit antidepressant-like responses in rodents, but if these actions are associated with its ability to afford neuroprotection against glutamate-induced toxicity still needs to be fully understood. Therefore, this study investigated the antidepressant-like and neuroprotective effects elicited by guanosine in mice and evaluated the possible involvement of NMDA receptors, glutamine synthetase, and GLT-1 in these responses. We found that guanosine (0.05 mg/kg, but not 0.01 mg/kg, p. o.) was effective in producing an antidepressant-like effect and protecting hippocampal and prefrontocortical slices against glutamate-induced damage. Our results also unveiled that ketamine (1 mg/kg, but not 0.1 mg/kg, i. p, an NMDA receptor antagonist) effectively elicited antidepressant-like actions and protected hippocampal and prefrontocortical slices against glutamatergic toxicity. Furthermore, the combined administration of sub-effective doses of guanosine (0.01 mg/kg, p. o.) with ketamine (0.1 mg/kg, i. p.) promoted an antidepressant-like effect and augmented glutamine synthetase activity and GLT-1 immunocontent in the hippocampus, but not in the prefrontal cortex. Our results also showed that the combination of sub-effective doses of ketamine and guanosine, at the same protocol schedule that exhibited an antidepressant-like effect, effectively abolished glutamate-induced damage in hippocampal and prefrontocortical slices. Our in vitro results reinforce that guanosine, ketamine, or sub-effective concentrations of guanosine plus ketamine protect against glutamate exposure by modulating glutamine synthetase activity and GLT-1 levels. Finally, molecular docking analysis suggests that guanosine might interact with NMDA receptors at the ketamine or glycine/d-serine co-agonist binding sites. These findings provide support for the premise that guanosine has antidepressant-like effects and should be further investigated for depression management.

Distinctive effects of NMDA receptor modulators on cerebral microcirculation in a schizophrenia mouse model

Substantial evidence demonstrates that schizophrenia patients have altered cerebral microcirculation. However, little is known regarding how cerebral microcirculatory blood flow (microCBF) changes in schizophrenia. Here, using time-lapse two-photon imaging of individual capillaries, we demonstrated a substantial decrease in cerebral microcirculation in a mouse model of schizophrenia. The involvement of NMDA receptor (NMDAR) functions was investigated to understand further the mechanism of microcirculation reduction in this animal model. Administration of D-serine, a selective full agonist at the glycine site of NMDAR, significantly increased the microCBF in the schizophrenia mouse. Interestingly, administration of GNE-8324, a GluN2A-selective positive allosteric modulator that selectively enhances NMDAR-mediated synaptic responses in inhibitory but not excitatory neurons, had no effect on the microCBF of the schizophrenia mice. Together, these data indicated that NMDAR participated in the regulation of microcirculation in schizophrenia using a mechanism dependent on the tonic NMDAR signaling and the selective modulation of inhibitory neuron activity. Further studies are warranted to establish NMDAR's role in modulating microcirculation in schizophrenia.

The Emerging Role of N-Methyl-D-Aspartate (NMDA) Receptors in the Cardiovascular System: Physiological Implications, Pathological Consequences, and Therapeutic Perspectives

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate, mediate the slow component of excitatory neurotransmission in the central nervous system (CNS), and induce long-term changes in synaptic plasticity. NMDARs are non-selective cation channels that allow the influx of extracellular Na+ and Ca2+ and control cellular activity via both membrane depolarization and an increase in intracellular Ca2+ concentration. The distribution, structure, and role of neuronal NMDARs have been extensively investigated and it is now known that they also regulate crucial functions in the non-neuronal cellular component of the CNS, i.e., astrocytes and cerebrovascular endothelial cells. In addition, NMDARs are expressed in multiple peripheral organs, including heart and systemic and pulmonary circulations. Herein, we survey the most recent information available regarding the distribution and function of NMDARs within the cardiovascular system. We describe the involvement of NMDARs in the modulation of heart rate and cardiac rhythm, in the regulation of arterial blood pressure, in the regulation of cerebral blood flow, and in the blood-brain barrier (BBB) permeability. In parallel, we describe how enhanced NMDAR activity could promote ventricular arrhythmias, heart failure, pulmonary artery hypertension (PAH), and BBB dysfunction. Targeting NMDARs could represent an unexpected pharmacological strategy to reduce the growing burden of several life-threatening cardiovascular disorders.

Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a major cause of blindness. Recent studies have reported impaired glycolysis in AMD patients with a high lactate/pyruvate ratio. Elevated homocysteine (Hcy) (Hyperhomocysteinemia, HHcy) was observed in several clinical studies, reporting an association between HHcy and AMD. We established the effect of HHcy on barrier function, retinal pigment epithelium (RPE) structure, and induced choroidal neovascularization (CNV) in mice. We hypothesize that HHcy contributes to AMD by inducing a metabolic switch in the mitochondria, in which cells predominantly produce energy by the high rate of glycolysis, or "Warburg", effect. Increased glycolysis results in an increased production of lactate, cellular acidity, activation of angiogenesis, RPE barrier dysfunction, and CNV. Evaluation of cellular energy production under HHcy was assessed by seahorse analysis, immunofluorescence, and western blot experiments. The seahorse analysis evaluated the extracellular acidification rate (ECAR) as indicative of glycolysis. HHcy showed a significant increase in ECAR both in vivo using (Cystathionine β-synthase) cbs+/- and cbs-/- mice retinas and in vitro (Hcy-treated ARPE-19) compared to wild-type mice and RPE cells. Moreover, HHcy up-regulated glycolytic enzyme (Glucose transporter-1 (GlUT-1), lactate dehydrogenase (LDH), and hexokinase 1 (HK1)) in Hcy-treated ARPE-19 and primary RPE cells isolated from cbs+/+, cbs+/-, and cbs-/- mice retinas. Inhibition of GLUT-1 or blocking of N-methyl-D-aspartate receptors (NMDAR) reduced glycolysis in Hcy-treated RPE and improved albumin leakage and CNV induction in Hcy-injected mice eyes. The current study suggests that HHcy causes a metabolic switch in the RPE cells from mitochondrial respiration to glycolysis during AMD and confirms the involvement of NMDAR in this process. Therefore, targeting Glycolysis or NMDAR could be a novel therapeutic target for AMD.

An IGFBP2-derived peptide promotes neuroplasticity and rescues deficits in a mouse model of Phelan-McDermid syndrome.

We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.

Delayed Impairment of Hippocampal Synaptic Plasticity after Pentylenetetrazole-Induced Seizures in Young Rats.

Data on the long-term consequences of a single episode of generalized seizures in infants are inconsistent. In this study, we examined the effects of pentylenetetrazole-induced generalized seizures in three-week-old rats. One month after the seizures, we detected a moderate neuronal loss in several hippocampal regions: CA1, CA3, and hilus, but not in the dentate gyrus. In addition, long-term synaptic potentiation (LTP) was impaired. We also found that the mechanism of plasticity induction was altered: additional activation of metabotropic glutamate receptors (mGluR1) is required for LTP induction in experimental rats. This disturbance of the plasticity induction mechanism is likely due to the greater involvement of perisynaptic NMDA receptors compared to receptors located in the core part of the postsynaptic density. This hypothesis is supported by experiments with selective blockades of core-located NMDA receptors by the use-dependent blocker MK-801. MK-801 had no effect on LTP induction in experimental rats and suppressed LTP in control animals. The weakening of the function of core-located NMDA receptors may be due to the disturbed clearance of glutamate from the synaptic cleft since the distribution of the astrocytic glutamate transporter EAAT2 in experimental animals was found to be altered.

Targeting NMDA Receptors in Emotional Disorders: Their Role in Neuroprotection.

Excitatory glutamatergic neurotransmission mediated through N-methyl-D-Aspartate (NMDA) receptors (NMDARs) is essential for synaptic plasticity and neuronal survival. While under pathological states, abnormal NMDAR activation is involved in the occurrence and development of psychiatric disorders, which suggests a directional modulation of NMDAR activity that contributes to the remission and treatment of psychiatric disorders. This review thus focuses on the involvement of NMDARs in the pathophysiological processes of psychiatric mood disorders and analyzes the neuroprotective mechanisms of NMDARs. Firstly, we introduce NMDAR-mediated neural signaling pathways in brain function and mood regulation as well as the pathophysiological mechanisms of NMDARs in emotion-related mental disorders such as anxiety and depression. Then, we provide an in-depth summary of current NMDAR modulators that have the potential to be developed into clinical drugs and their pharmacological research achievements in the treatment of anxiety and depression. Based on these findings, drug-targeting for NMDARs might open up novel territory for the development of therapeutic agents for refractory anxiety and depression.

The Role of the NMDA Receptor in the Anticonvulsant Effect of Ellagic Acid in Pentylenetetrazole-Induced Seizures in Male Mice.

Methods In this experimental study, 64 mice were divided into 8 groups and received the following: normal saline; EA at doses of 6.25, 12.5, and 25 mg/kg; NMDA agonist at a dose of 75 mg/kg; NMDA antagonist (ketamine) at a dose of 0.5 mg/kg; an effective dose of EA plus NMDA agonist; and a subeffective dose of EA plus ketamine. We induced seizure using intravenous administration of PTZ. 60 minutes before induction of seizure, drugs were administrated. Duration lasts to seizure-induced was measured. Finally, the gene expression of NMDA receptor subunits (Nr2a and Nr2b) was assessed in the prefrontal cortex. Results Results showed that EA increased the seizure threshold and decreased the expression of Nr2a and Nr2b. We determined that ketamine potentiated and NMDA attenuated the effects of subeffective and effective doses of EA. Conclusion EA probably via attenuation of the NMDA-R pathway possesses an anticonvulsant effect in PTZ-induced seizure in mice.

Discrimination of motor and sensorimotor effects of phencyclidine and MK-801: Involvement of GluN2C-containing NMDA receptors in psychosis-like models

Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in reticular thalamic GABAergic neurons. GluN2C subunits are densely expressed in thalamus and cerebellum. Therefore, we examined their involvement in the behavioral and functional effects elicited by PCP and MK-801 using GluN2C knockout (GluN2CKO) and wild-type mice, under the working hypothesis that psychotomimetic effects should be attenuated in mutant mice. PCP and MK-801 induced a disorganized and meandered hyperlocomotion in both genotypes. Interestingly, stereotyped behaviors like circling/rotation, rearings and ataxia signs were dramatically reduced in GluN2CKO mice, indicating a better motor coordination in absence of GluN2C subunits. In contrast, other motor or sensorimotor (pre-pulse inhibition of the startle response) aspects of the behavioral syndrome remained unaltered by GluN2C deletion. PCP and MK-801 evoked a general pattern of c-fos activation in mouse brain (including thalamo-cortical networks) but not in the cerebellum, where they markedly reduced c-fos expression, with significant genotype differences paralleling those in motor coordination. Finally, resting-state fMRI showed an enhanced cortico-thalamic-cerebellar connectivity in GluN2CKO mice, less affected by MK-801 than controls.Hence, the GluN2C subunit allows the dissection of the behavioral alterations induced by PCP and MK-801, showing that some motor effects (in particular, motor incoordination), but not deficits in sensorimotor gating, likely depend on GluN2C-containing NMDA-R blockade in cerebellar circuits.

Choice-selective sequences dominate in cortical relative to thalamic inputs to NAc to support reinforcement learning.

SUMMARYHow are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement-learning algorithms, in both a circuit model based on synaptic plasticity and one based on neural dynamics. Finally, we test and confirm a prediction of our circuit models by direct manipulation of nucleus accumbens input neurons.

Prediction Error Determines Whether NMDA Receptors in the Basolateral Amygdala Complex Are Involved in Pavlovian Fear Conditioning.

It is widely accepted that activation of NMDA receptors (NMDAR) is necessary for the formation of fear memories in the basolateral amygdala complex (BLA). This acceptance is based on findings that blockade of NMDAR in the BLA disrupts Pavlovian fear conditioning in rodents when initially innocuous stimuli are paired with aversive and unexpected events (surprising foot shock). The present study challenges this acceptance by showing that the involvement of NMDAR in Pavlovian fear conditioning is determined by prediction errors in relation to aversive events. In the initial experiments, male rats received a BLA infusion of the NMDAR antagonist, D-AP5 and were then exposed to pairings of a novel target stimulus and foot shock. This infusion disrupted acquisition of fear to the target when the shock was surprising (experiments 1a, 1b, 2a, 2b, 3a, and 3b) but spared fear to the target when the shock was expected based on the context, time and other stimuli that were present (experiments 1a and 1b). Under the latter circumstances, fear to the target required activation of calcium-permeable AMPAR (CP-AMPA; experiments 4a, 4b, and 4c), which, using electrophysiology, were shown to regulate the activity of interneurons in the BLA (experiment 5). Thus, NMDAR activation is not required for fear conditioning when danger occurs as expected given the context, time and stimuli present, but is required for fear conditioning when danger occurs unexpectedly. These findings are related to current theories of NMDAR function and ways that prediction errors might influence the substrates of fear memory formation in the BLA.SIGNIFICANCE STATEMENT It is widely accepted that NMDA receptors (NMDAR) in the basolateral amygdala complex (BLA) are activated by pairings of a conditioned stimulus (CS) and an aversive unconditioned (US) stimulus, leading to the synaptic changes that underlie formation of a CS-US association. The present findings are significant in showing that this theory is incomplete. When the aversive US is unexpected, animals encode all features of the situation (context, time and stimuli present) as a new fear/threat memory, which is regulated by NMDAR in the BLA. However, when the US is expected based on the context, time and stimuli present, the new fear memory is assimilated into networks that represent those features, which occurs independently of NMDAR activation in the BLA.

Differential Effects of N-methyl-D-aspartate Receptors Activation in the Insular Cortex during Memory Formation and Updating of a Motivational Conflict Task

Recognizing and weighing the value of stimuli is necessary for survival, as it allows living things to respond quickly and adequately to new experiences by comparing them with previous ones. Recent evidence shows that context change could affect flavor learning, suggesting a more intricate scenario during complex associations of stimuli with opposite or different valence in a motivational conflict task. Furthermore, linked to the ability to weigh the value of stimuli is the ability to predict the consequences associated with them from previous experiences. The insular cortex (IC) is a brain hub connecting and integrating different sensory, emotional, motivational, and cognitive processing systems. In this regard, previous evidence indicates that glutamatergic activity in this area, mediated by N-methyl-D-aspartate receptors (NMDARs), could be important during positive or negative valence encoding. Hence, the present study examines the involvement of NMDARs in the IC during a complex association of stimuli with opposite valence through the modified inhibitory avoidance (MIA) task and memory updating of a previously learned appetitive context during latent inhibition of the MIA process. This study demonstrates that during a motivational conflict-learning task with stimuli of opposite valences, avoidance memory formation will prevail. NMDARs activation in the IC decreases avoidance memory formation during a complex task (MIA) but not memory formation for an appetitive context. Furthermore, NMDARs activation does not affect the transition from appetitive to aversive learning. Overall, our results propose a different IC-NMDARs function during novel learning and memory updating.

Structural and Functional Coupling of Calcium-Activated BK Channels and Calcium-Permeable Channels Within Nanodomain Signaling Complexes.

Biochemical and functional studies of ion channels have shown that many of these integral membrane proteins form macromolecular signaling complexes by physically associating with many other proteins. These macromolecular signaling complexes ensure specificity and proper rates of signal transduction. The large-conductance, Ca2+-activated K+ (BK) channel is dually activated by membrane depolarization and increases in intracellular free Ca2+ ([Ca2+]i). The activation of BK channels results in a large K+ efflux and, consequently, rapid membrane repolarization and closing of the voltage-dependent Ca2+-permeable channels to limit further increases in [Ca2+]i. Therefore, BK channel-mediated K+ signaling is a negative feedback regulator of both membrane potential and [Ca2+]i and plays important roles in many physiological processes and diseases. However, the BK channel formed by the pore-forming and voltage- and Ca2+-sensing α subunit alone requires high [Ca2+]i levels for channel activation under physiological voltage conditions. Thus, most native BK channels are believed to co-localize with Ca2+-permeable channels within nanodomains (a few tens of nanometers in distance) to detect high levels of [Ca2+]i around the open pores of Ca2+-permeable channels. Over the last two decades, advancement in research on the BK channel’s coupling with Ca2+-permeable channels including recent reports involving NMDA receptors demonstrate exemplary models of nanodomain structural and functional coupling among ion channels for efficient signal transduction and negative feedback regulation. We hereby review our current understanding regarding the structural and functional coupling of BK channels with different Ca2+-permeable channels.

Developmental stage-specific involvement of NMDA receptor hypofunction in risk formation for psychiatric disorders

Successful maturation of the brain relies on complex interactions between various neurotransmitter signaling. Glutamate, a major excitatory neurotransmitter in mammalian central nervous system, and an ionotropic glutamate receptor subtype, N-methyl-D-aspartate (NMDA) receptor, play essential roles in brain development. It has been reported that animals treated with an NMDA receptor antagonist during neonatal period show various behavioral abnormalities relevant to neurodevelopmental disorders in later life. We previously found that NMDA receptor blockade during neonatal period, but not adulthood, caused significant cognitive impairment in rats. Thus, the adverse effects of NMDA receptor blockade are dependent on the time when the treatment is administered. We further investigated the precise timing that NMDA receptors are involved in the development of cognitive functions, and the mechanism underlying the vulnerability of the immature brain to NMDA receptor blockade. In this symposium, we discuss the importance of the second postnatal week on the development of hippocampus-dependent learning in rats. We also discuss the involvement of NR2A-containing NMDA receptors in the formation of schizophrenia-related behavioral changes induced by neonatal NMDA receptor blockade.

Maturation of GABAergic Synaptic Transmission in Immature Neocortical Fast-Spiking Interneurons Involves NMDA Receptor Recruitment of Cav2.1 Channels

Maturation of GABAergic Synaptic Transmission in Immature Neocortical Fast-Spiking Interneurons Involves NMDA Receptor Recruitment of Cav2.1 Channels

Role of NMDA Receptors in Alzheimer's Disease Pathology and Potential NMDA Receptor Blockers from Medicinal Plants - A Review

<p>Alzheimer’s disease is responsible for 60-70 percent of dementia cases worldwide. Globally, there are 24.3 million cases. Researchers have attempted to develop multi-target medications to suppress several mechanisms in Alzheimer’ Disease, like protein mis-folding and related beta amyloid aggregation, oxidative stress, and decreasing Acetyl choline levels. NMDA-mediated neurotoxicity is often linked to cognitive impairment, as shown in Alzheimer’s disease. NMDA receptors found to have to connection with beta amyloid peptide and tau protein deposition which are major characteristics of Alzheimer’s disease. NMDA receptor antagonists are a viable therapy option for a many neurological disorders, as well as Alzheimer’s disease. Currently, majority of the drugs used in the management of Alzheimer’s disease are Acetyl choline Esterase inhibitors. Memantine is the only approved NMDA blocker, to be used in Alzheimer’s disease, which is found to be effective only to a certain extend. There is a need for better therapeutic agents belonging to this class. This paper intends to provide a rapid reference about the involvement of NMDA receptors in the pathogenesis of Alzheimer’s disease, as well as phyto constituents that have been identified to inhibit NMDA receptors.</p>

TH79. MITOCHONDRIAL DNA ALTERATIONS IN THE POSTMORTEM BRAIN OF PSYCHIATRIC DISEASES: A SYSTEMATIC REVIEW

It has previously been hypothesized that hyperactivity of central auditory neurons following exposure to intense noise is a consequence of synaptic alterations. Recent studies suggest the involvement of NMDA receptors in the induction of this hyperactive state. NMDA receptors can mediate long term changes in the excitability of neurons through their involvement in excitotoxic injury and long term potentiation and depression. In this study, we examined the effect of administering an NMDA receptor blocker on the induction of hyperactivity in the dorsal cochlear nucleus (DCN) following intense sound exposure. Our prediction was that if hyperactivity induced by intense sound exposure is dependent on NMDA receptors, then blocking these receptors by administering an NMDA receptor antagonist just before animals are exposed to intense sound should reduce the degree of hyperactivity that subsequently emerges. We compared the levels of hyperactivity that develop in the DCN after intense sound exposure to activity recorded in control animals that were not sound exposed. One group of animals to be sound exposed received intraperitoneal injection of MK-801 twenty minutes preceding the sound exposure, while the other group received injection of saline. Recordings performed in the DCN 26–28 days post-exposure revealed increased response thresholds and widespread increases in spontaneous activity in the saline-treated animals that had been sound exposed, consistent with earlier studies. The animals treated with MK-801 preceding sound exposure showed similarly elevated thresholds but an attenuation of hyperactivity in the DCN; the attenuation was most robust in the high frequency half of the DCN, but lower levels of hyperactivity were also found in the low frequency half. These findings suggest that NMDA receptors are an important component of the hyperactivity-inducing mechanism following intense sound exposure. They further suggest that blockade of NMDA receptors may offer a useful therapeutic approach to preventing induction of noise-induced hyperactivity-related hearing disorders, such as tinnitus and hyperacusis.