NMDARs in Alzheimer's Disease: Between Synaptic and Extrasynaptic Membranes.

N-methyl-D-aspartate receptors (NMDARs) are glutamate receptors with key roles in synaptic communication and plasticity. The activation of synaptic NMDARs initiates plasticity and stimulates cell survival. In contrast, the activation of extrasynaptic NMDARs can promote cell death underlying a potential mechanism of neurodegeneration occurring in Alzheimer's disease (AD). The distribution of synaptic versus extrasynaptic NMDARs has emerged as an important parameter contributing to neuronal dysfunction in neurodegenerative diseases including AD. Here, we review the concept of extrasynaptic NMDARs, as this population is present in numerous neuronal cell membranes but also in the membranes of various non-neuronal cells. Previous evidence regarding the membranal distribution of synaptic versus extrasynaptic NMDRs in relation to AD mice models and in the brains of AD patients will also be reviewed.

GluN2A: A Promising Target for Developing Novel Antidepressants.

BACKGROUND: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems regarding mental health care. It is now well established that N-methyl D-aspartate receptor (NMDAR) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS), and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. METHODS: We reviewed several past studies to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. RESULTS: These evidence suggests that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. CONCLUSIONS: Specific inhibition of the GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.

Discovery of GluN2A subtype-selective N-methyl-d-aspartate (NMDA) receptor ligands.

The N-methyl-d-aspartate (NMDA) receptors, which belong to the ionotropic Glutamate receptors, constitute a family of ligand-gated ion channels. Within the various subtypes of NMDA receptors, the GluN1/2A subtype plays a significant role in central nervous system (CNS) disorders. The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors, encompassing negative allosteric modulators (NAMs), positive allosteric modulators (PAMs) and competitive antagonists. Moreover, the ligands' structure-activity relationships (SARs) and the binding models of representative ligands are also discussed, providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

Homocysteine-induced sustained GluN2A NMDA receptor stimulation leads to mitochondrial ROS generation and neurotoxicity.

Homocysteine, a sulfur-containing amino acid derived from methionine metabolism, is a known agonist of N-methyl-D-aspartate receptor (NMDAR) and is involved in neurotoxicity. Our previous findings showed that neuronal exposure to elevated homocysteine levels leads to sustained low-level increase in intracellular Ca2+, which is dependent on GluN2A subunit-containing NMDAR (GluN2A-NMDAR) stimulation. These studies further showed a role of ERK MAPK in homocysteine-GluN2A-NMDAR-mediated neuronal death. However, the intracellular mechanisms associated with such sustained GluN2A-NMDAR stimulation and subsequent Ca2+ influx have remained unexplored. Using live-cell imaging with Fluo3-AM and biochemical approaches, we show that homocysteine-GluN2A NMDAR-induced initial Ca2+ influx triggers sequential phosphorylation and subsequent activation of the proline rich tyrosine kinase 2 (Pyk2) and Src family kinases, which in turn phosphorylates GluN2A-Tyr1325 residue of GluN2A-NMDARs to maintain channel activity. The continuity of this cycle of events leads to sustained Ca2+ influx through GluN2A-NMDAR. Our findings also show that lack of activation of the regulatory tyrosine phosphatase STEP, which can limit Pyk2 and Src family kinase activity further contributes to the maintenance of this cycle. Additional studies using live-cell imaging of neurons expressing a redox-sensitive GFP targeted to the mitochondrial matrix show that treatment with homocysteine leads to a progressive increase in mitochondrial reactive oxygen species generation, which is dependent on GluN2A-NMDAR-mediated sustained ERK MAPK activation. This later finding demonstrates a novel role of GluN2A-NMDAR in homocysteine-induced mitochondrial ROS generation and highlights the role of ERK MAPK as the intermediary signaling pathway between GluN2A-NMDAR stimulation and mitochondrial reactive oxygen species generation.

Differential depletion of GluN2A induces heterogeneous schizophrenia-related phenotypes in mice.

BACKGROUND: Schizophrenia, a debilitating psychiatric disorder, displays considerable interindividual variation in clinical presentations. The ongoing debate revolves around whether this heterogeneity signifies a continuum of severity linked to a singular causative factor or a collection of distinct subtypes with unique origins. Within the realm of schizophrenia, the functional impairment of GluN2A, a subtype of the NMDA receptor, has been associated with an elevated risk. Despite GluN2A's expression across various neuronal types throughout the brain, its specific contributions to schizophrenia and its involvement in particular cell types or brain regions remain unexplored. METHODS: We generated age-specific, cell type-specific or brain region-specific conditional knockout mice targeting GluN2A and conducted a comprehensive analysis using tests measuring phenotypes relevant to schizophrenia. FINDINGS: Through the induction of germline ablation of GluN2A, we observed the emergence of numerous schizophrenia-associated abnormalities in adult mice. Intriguingly, GluN2A knockout performed at different ages, in specific cell types and within distinct brain regions, we observed overlapping yet distinct schizophrenia-related phenotypes in mice. INTERPRETATION: Our interpretation suggests that the dysfunction of GluN2A is sufficient to evoke heterogeneous manifestations associated with schizophrenia, indicating that GluN2A stands as a prominent risk factor and a potential therapeutic target for schizophrenia. FUNDING: This project received support from the Shanghai Municipal Science and Technology Major Project (Grant No. 2019SHZDZX02) awarded to Y.C. and the Natural Science Foundation of Shanghai (Grant No. 19ZR1468600 and 201409003800) awarded to G.Y.

Role of NMDA Receptor in High-Pressure Neurological Syndrome and Hyperbaric Oxygen Toxicity.

Professional divers exposed to pressures greater than 11 ATA (1.1 MPa) may suffer from high-pressure neurological syndrome (HPNS). Divers who use closed-circuit breathing apparatus and patients and medical attendants undergoing hyperbaric oxygen therapy (HBOT) face the risk of CNS hyperbaric oxygen toxicity (HBOTx) at oxygen pressure above 2 ATA (0.2 MPa). Both syndromes are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits, and N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in provoking them. Various NMDAR subtypes respond differently under hyperbaric conditions. The augmented currents observed only in NMDAR containing GluN2A subunit increase glutamatergic synaptic activity and cause dendritic hyperexcitability and abnormal neuronal activity. Removal of the resting Zn2+ voltage-independent inhibition exerted by GluN2A present in the NMDAR is the major candidate for the mechanism underlying the increase in receptor conductance. Therefore, this process should be the main target for future research aiming at developing neuroprotection against HPNS and HBOTx.

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.

N-methyl-D-aspartate receptors (NMDARs) are ion channels that respond to the neurotransmitter glutamate, playing a crucial role in the permeability of calcium ions and excitatory neurotransmission in the central nervous system (CNS). Composed of various subunits, NMDARs are predominantly formed by two obligatory GluN1 subunits (with eight splice variants) along with regulatory subunits GluN2 (GluN2A-2D) and GluN3 (GluN3A-B). They are widely distributed throughout the CNS and are involved in essential functions such as synaptic transmission, learning, memory, plasticity, and excitotoxicity. The presence of GluN2A and GluN2B subunits is particularly important for cognitive processes and has been strongly implicated in neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. Understanding the roles of GluN2A and GluN2B NMDARs in neuropathologies provides valuable insights into the underlying causes and complexities of major nervous system disorders. This knowledge is vital for the development of selective antagonists targeting GluN2A and GluN2B subunits using pharmacological and molecular methods. Such antagonists represent a promising class of NMDA receptor inhibitors that have the potential to be developed into neuroprotective drugs with optimal therapeutic profiles.

Striatal synaptic changes and behavior in adult mouse upon prenatal exposure to valproic acid.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by persistent deficits in social communication and social interaction. Altered synaptogenesis and aberrant connectivity responsible for social behavior and communication have been reported in autism pathogenesis. Autism has a strong genetic and heritable component; however, environmental factors including toxins, pesticides, infection and in utero exposure to drugs such as VPA have also been implicated in ASD. Administration of VPA during pregnancy has been used as a rodent model to study pathophysiological mechanisms involved in ASD, and in this study, we used the mouse model of prenatal exposure to VPA to assess the effects on striatal and dorsal hippocampus function in adult mice. Alterations in repetitive behaviors and shift habits were observed in mice prenatally exposed to VPA. In particular, such mice presented a better performance in learned motor skills and cognitive deficits in Y-maze learning frequently associated with striatal and hippocampal function. These behavioral changes were associated with a decreased level of proteins involved in the formation and maintenance of excitatory synapses, such as Nlgn-1 and PSD-95. In conclusion, motor skill abilities, repetitive behaviors, and impaired flexibility to shift habits are associated with reduced striatal excitatory synaptic function in the adult mouse prenatally exposed to VPA.

Long-term α5 GABA A receptor negative allosteric modulator treatment reduces NMDAR-mediated neuronal excitation and maintains basal neuronal inhibition.

α5 subunit-containing GABA type-A receptors (α5 GABAARs) are enriched in the hippocampus and play critical roles in neurodevelopment, synaptic plasticity, and cognition. α5 GABAAR preferring negative allosteric modulators (α5 NAMs) show promise mitigating cognitive impairment in preclinical studies of conditions characterized by excess GABAergic inhibition, including Down syndrome and memory deficits post-anesthesia. However, previous studies have primarily focused on acute application or single-dose α5 NAM treatment. Here, we measured the effects of chronic (7-day) in vitro treatment with L-655,708 (L6), a highly selective α5 NAM, on glutamatergic and GABAergic synapses in rat hippocampal neurons. We previously showed that 2-day in vitro treatment with L6 enhanced synaptic levels of the glutamate NMDA receptor (NMDAR) GluN2A subunit without modifying surface α5 GABAAR expression, inhibitory synapse function, or L6 sensitivity. We hypothesized that chronic L6 treatment would further increase synaptic GluN2A subunit levels while maintaining GABAergic inhibition and L6 efficacy, thus increasing neuronal excitation and glutamate-evoked intracellular calcium responses. Immunofluorescence experiments revealed that 7-day L6 treatment slightly increased the synaptic levels of gephyrin and surface α5 GABAARs. Functional studies showed that chronic α5 NAM treatment did not alter inhibition or α5 NAM sensitivity. Surprisingly, chronic L6 exposure decreased surface levels of GluN2A and GluN2B subunits, concurrent with reduced NMDAR-mediated neuronal excitation as seen by faster synaptic decay rates and reduced glutamate-evoked calcium responses. Together, these results show that chronic in vitro treatment with an α5 NAM leads to subtle homeostatic changes in inhibitory and excitatory synapses that suggest an overall dampening of excitability.

Successful Treatment of a Child With Epileptic Encephalopathy With Spike-Wave Activation in Sleep and GRIN2A Variant Using Sulthiame.

Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) and developmental EE-SWAS (DEE-SWAS) are characterized by variable combinations of cognitive, language, behavioral, and/or motor regression associated with continuous or near-continuous diffuse spike-and-wave complexes during sleep. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) variants have been associated with EE-SWAS. It encodes the most relevant GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR). Sulthiame reduces NMDAR-mediated neuronal excitability and has been progressively used as monotherapy in self-limited epilepsy with centrotemporal spikes (SeLECTS) or as add-ontherapy in EE-SWAS/DEE-SWAS. A five-year-old female, with family history of epilepsy, was initially diagnosed with SeLECTS and medicated with valproic acid (VPA). One year later, she presented a focal to bilateral tonic-clonic seizure during sleep and learning difficulty. The electroencephalogram revealed continuous spike-and-wave during sleep leading to the diagnosis of EE-SWAS. Prednisolone was effective, but there was repeated recurrence after its discontinuation and associated adverse effects. As an alternative, sulthiame was added to VPA. Four years later, she remains clinically stable. Genetic testing revealed a GRIN2A missense variant, C.3228C>A (p.Asn1076Lys). Sulthiame appeared effective in this recurrent EE-SWAS child, who presented a GRIN2A missense variant with possible NMDAR gain-of-function and adverse effects of corticosteroids. Functional studies​​​​​​​ of GRIN2A variants might become a future tool for individualized therapies.

Efavirenz restored NMDA receptor dysfunction and inhibited epileptic seizures in GluN2A/Grin2a mutant mice.

Introduction: N-methyl-D-aspartate receptor (NMDAR) is one of the main receptor of the excitatory neurotransmitter glutamate in the brain, which is the key determinant of the excitatory/inhibitory balance of neural network. GluN2A/GRIN2A is one of the subunits of NMDAR and plays an important role in epilepsy. Approximately 78% of patients with GluN2A/Grin2a mutations have epilepsy, and the underlying mechanism of this association is not well characterized. Methods: We constructed a mouse model of hyperthermic seizure, and conducted in vitro and in vivo electrophysiological and behavioral studies to clarify the pathogenic characteristics and mechanism of GluN2A/GRIN2A-V685G mutation. In addition, the drug efavirenz (EFV), which is used to treat HIV infection, was administrated to mutant animals to assess whether it can restore the loss of function. Results: Mutant mice showed no significant change in the mRNA or protein expressions of NMDAR compared with wild type (WT) mice. Mice with GluN2A/GRIN2A-V685G mutation exhibited shorter latency to seizure, increased frequency of seizure-like events, decreased peak current and current area of NMDAR excitatory postsynaptic current, and decreased event frequency of micro-inhibitory postsynaptic current, compared to WT mice. They also exhibited decreased threshold, increased amplitude, increased input resistance, and increased root number of action potential. EFV administration reversed these changes. The loss-of-function (LoF) mutation of NMDAR changed the excitatory/inhibitory balance of neural network, rendering animal more prone to seizures. Discussion: EFV was indicated to hold its potential in the treatment of inherited epilepsy.

Design and synthesis of novel GluN2A NMDAR positive allosteric modulators via scaffold hopping strategy as anti-stroke therapeutic agents.

NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo . Activation of NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action, whereas over activating GluN2B-containing receptor results in excitotoxicity, increasing neuronal apoptosis. Our previous study has identified Npam 43 as a NMDAR positive allosteric modulators. However, the cis-trans isomerization impedes the development of Npam 43 as potential neuroprotective agents. To discover more potent and selective GluN2A NMDAR positive allosteric modulators, 38 derivatives were synthesized and evaluated their neuroprotective effect on glutamate-exposed PC-12 cells. The allosteric activities of compounds were evaluated using calcium imaging approaches. Among them, compound 5c exhibit GluN1/2A selectivity over GluN1/2B and show neuroprotective activity in vitro and in vivo. This study reported a series of GluN1/2A positive allosteric modulators as neuroprotective agents, and provided a potential opportunity to discover new drugs for stroke treatment.

Design and synthesis of 6-methylpyridin-2-one derivatives as novel and potent GluN2A positive allosteric modulators for the treatment of cognitive impairment.

N-Methyl-D-aspartate receptors (NMDARs) are key regulators of synaptic plasticity in the central nervous system. Potentiation of NMDARs containing GluN2A subunit has been recently recognized as a promising therapeutic approach for neurological disorders. We identified a novel series of GluN2A positive allosteric modulator (PAM) with a pyridin-2-one scaffold. Initial lead compound 1 was discovered through in silico-based screening of virtual ligands with various monocyclic scaffolds. GluN2A PAM activity was increased by introduction of a methyl group at the 6-position of the pyridin-2-one ring and a cyano group in the side chain. Modification of the aromatic ring led to the identification of potent and brain-penetrant 6-methylpyridin-2-one 17 with a negligible binding activity for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Oral administration of 17 significantly enhanced rat hippocampal long-term potentiation (LTP). Thus, 17 would be a useful in vivo pharmacological tool to investigate complex NMDAR functions for the discovery of therapeutics toward diseases associated with NMDAR dysfunction.

Progresses in GluN2A-containing NMDA Receptors and their Selective Regulators.

NMDA receptors play an important physiological role in regulating synaptic plasticity, learning and memory. GluN2A subunits are the most abundant functional subunits of NMDA receptors expressed in mature brain, and their dysfunction is related to various neurological diseases. According to subunit composition, GluN2A-containing NMDA receptors can be divided into two types: diheteromeric and triheteromeric receptors. In this review, the expression, functional and pharmacological properties of different kinds of GluN2A-containing NMDA receptors as well as selective GluN2A regulators were described to further understand this type of NMDA receptors.

GluN2A Mediates PS-Induced Depressive-Like Behavior by Activating CaMKII and Inhibiting Myelinization.

BACKGROUND: Prenatal stress (PS) can induce depression in offspring, but the underlying mechanisms are still unknown. OBJECTIVE: The aim of this work was to investigate the mechanism that underlies PS-induced depressive-like behavior in offspring. METHODS: A prenatal restraint stress procedure was developed in which pregnant rats at GD14 to GD20 were placed head-first into a well-ventilated bottle three times each day and for 45 min each time. Depressive-like behavior in the male offspring was examined using the sucrose preference test (SPT) and the forced swim test (FST). The level of glutamate and the expression levels of GluN2A, p-CaMKII and myelin basic protein (MBP) in the hippocampus of PS-susceptible (PS-S) offspring were also evaluated. To clarify the mechanism by which PS leads to depression in offspring, the effects of excessive corticosterone were also investigated using an in vitro "injured neuronal" model. RESULTS: The glutamate level in the hippocampus of PS-S male offspring was significantly elevated compared to controls. The expression levels of GluN2A and p-CaMKII were also altered. In addition, the optical density of MBP staining and the expression levels of MBP mRNA and MBP protein were decreased, demonstrating impaired myelinization in the hippocampus. Treatment of PS-S offspring with the GluN2A receptor antagonist NVP-AAM077 resulted in antidepressant-like effects in the FST, as well as rescue of the MBP and p-CaMKII abnormalities. CONCLUSIONS: These findings indicate that GluN2A is a promising target in the development of pharmacotherapies for PS-induced depression.

Intracellular zinc signaling influences NMDA receptor function by enhancing the interaction of ZnT1 with GluN2A.

Zinc, loaded into glutamate-containing presynaptic vesicles and released into the synapse in an activity-dependent manner, modulates neurotransmission through its actions on postsynaptic targets, prominently via high-affinity inhibition of GluN2A-containing NMDA receptors. Recently, we identified a postsynaptic transport mechanism that regulates endogenous zinc inhibition of NMDARs. In this new model of zinc regulation, the postsynaptic transporter ZnT1 mediates zinc inhibition of NMDARs by binding to GluN2A. Through this interaction, ZnT1, a transporter that moves zinc from the cytoplasm to the extracellular domain, generates a zinc microdomain that modulates NMDAR-mediated neurotransmission. As ZnT1 expression is transcriptionally driven by the metal-responsive transcription factor 1 (MTF-1), we found that intracellular zinc strongly drives MTF-1 in cortical neurons in vitro and increases the number of GluN2A-ZnT1 interactions, thereby enhancing tonic zinc inhibition of NMDAR-mediated currents. Importantly, this effect is absent when the interaction between GluN2A and ZnT1 is disrupted by a cell-permeable peptide. These results suggest that zinc-regulated gene expression can dynamically regulate NMDAR-mediated synaptic processes.

The Edible Seaweed Gelidium amansii Promotes Structural Plasticity of Hippocampal Neurons and Improves Scopolamine-Induced Learning and Memory Impairment in Mice.

BACKGROUND: Gelidium amansii has been gaining profound interest in East Asian countries due to its enormous commercial value for agar production and its extensive pharmacological properties. Previous studies have shown that the ethanol extract of Gelidium amansii (GAE) has promising neurotrophic effects in in vitro conditions. OBJECTIVES: The present study aimed at investigating the protective effects of GAE against scopolamine-induced cognitive deficits and its modulatory effects on hippocampal plasticity in mice. METHODS: For memory-related behavioral studies, the passive avoidance test and radial arm maze paradigm were conducted. The brain slices of the hippocampus CA1 neurons of experimental mice were then prepared to perform Golgi staining for analyzing spine density and its characteristic shape, and immunohistochemistry for assessing the expression of different pre- and postsynaptic proteins. RESULTS: Following oral administration of GAE (0.5 mg/g body weight), mice with memory deficits exhibited a significant increase in the latency time on the passive avoidance test and a decrease in the number of working and reference memory errors and latency time on the radial arm maze test. Microscopic observations of Golgi-impregnated tissue sections and immunohistochemistry of hippocampal slices showed that neurons from GAE-treated mice displayed higher spine density and spine dynamics, increased synaptic contact, and the recruitment of memory-associated proteins such as N-methyl-D-aspartate receptors (NR2A and NR2B) and postsynaptic density-95 (PSD-95) when compared with the control group. CONCLUSION: With these memory-protective functions and a modulatory role in underlying memory-related events, GAE could be a potential functional food and a promising source of pharmacological agents for the prevention and treatment of memory-related brain disorders.

GluN2A-Selective NMDA Receptor Antagonists: Mimicking the U-Shaped Bioactive Conformation of TCN-201 by a [2.2]Paracyclophane System.

Under physiological conditions, N-Methyl-D-Aspartate (NMDA) receptors play a crucial role for synaptic plasticity, long-term potentiation and long-term depression. However, overactivation of NMDA receptors can result in excitotoxicity, which is associated with various neurological and neurodegenerative diseases. The physiological properties of NMDA receptors are strongly dependent on the GluN2 subunit incorporated into the heterotetrameric NMDA receptor. Therefore, subtype selective NMDA receptor modulators are of high interest. Since prototypical GluN2A-NMDA receptor antagonists TCN-201 and its MPX-analogs adopt a U-shaped conformation within the binding pocket, paracyclophanes were designed containing the phenyl rings in an already parallel orientation. Docking studies of the designed paracyclophanes show a similar binding pose as TCN-201. [2.2]Paracyclophanes with a benzoate or benzamide side chain were prepared in four-step synthesis, respectively, starting with a radical bromination in benzylic 1-position of [2.2]paracyclophane. In two-electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNAs for the GluN1-4a and GluN2A subunits, the esters and amides (conc. 10 µM) did not show considerable inhibition of ion flux. It can be concluded that the GluN2A-NMDA receptor does not accept ligands with a paracyclophane scaffold functionalized in benzylic 1-position, although docking studies had revealed promising binding poses for benzoic acid esters and benzamides.

NX210c Peptide Promotes Glutamatergic Receptor-Mediated Synaptic Transmission and Signaling in the Mouse Central Nervous System.

NX210c is a disease-modifying dodecapeptide derived from the subcommissural organ-spondin that is under preclinical and clinical development for the treatment of neurological disorders. Here, using whole-cell patch-clamp recordings, we demonstrate that NX210c increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and GluN2A-containing N-methyl-D-aspartate receptor (GluN2A-NMDAR)-mediated excitatory postsynaptic currents in the brain. Accordingly, using extracellular field excitatory postsynaptic potential recordings, an enhancement of synaptic transmission was shown in the presence of NX210c in two different neuronal circuits. Furthermore, the modulation of synaptic transmission and GluN2A-NMDAR-driven signaling by NX210c restored memory in mice chronically treated with the NMDAR antagonist phencyclidine. Overall, by promoting glutamatergic receptor-related neurotransmission and signaling, NX210c represents an innovative therapeutic opportunity for patients suffering from CNS disorders, injuries, and states with crippling synaptic dysfunctions.

Effects of chronic vagal nerve stimulation in the treatment of ß-amyloid-induced neuropsychiatric symptoms.

Alzheimer's Disease (AD) is the leading cause of dementia and, at the time of diagnosis, half of AD patients display at least one neuropsychiatric symptom (NPS). However, there is no effective therapy for NPSs; furthermore, current treatments of NPSs accelerate cognitive decline. Due to the ineffectiveness and negative consequences of current treatments for NPSs, new approaches are strongly needed. Currently, indications for vagal nerve stimulation (VNS) include epilepsy, stroke rehabilitation and major depression but not NPSs or AD. Therefore, we investigated whether chronic VNS can treat NPSs in a rat model of AD. Here, we report the intracerebroventricular injection of amyloid-ß (Aß) results in depression-like behaviors and memory impairment in rats. Chronic VNS (0.8 mA, 500 µs, 30 Hz, 5 min/day) showed strong antidepressant and anxiolytic effects, and improved memory performance. Additionally, the anxiolytic effect of VNS was retained in the non-Aß-treated rats. VNS also decreased aggressiveness and increased locomotor activity in both Aß-treated and non-Aß-treated rats. Recent studies showed VNS alters glutamatergic receptor levels, thus levels of GluA1, GluN2A, and GluN2B were determined. A significant reduction in GluN2B levels was seen in the hippocampus of VNS-treated groups which may relate to the anxiolytic effects and increased locomotor activity of VNS. In conclusion, VNS could be an effective treatment of NPSs, especially depression and anxiety, in AD patients without impairing cognition.