Loss of TDP-43 function underlies hippocampal and cortical synaptic deficits in TDP-43 proteinopathies.

TDP-43 proteinopathy is linked to neurodegenerative diseases that feature synaptic loss in the cortex and hippocampus, although it remains unclear how TDP-43 regulates mature synapses. We report that, in adult mouse hippocampus, TDP-43 knockdown, but not overexpression, induces robust structural and functional damage to excitatory synapses, supporting a role for TDP-43 in maintaining mature synapses. Dendritic spine loss induced by TDP-43 knockdown is rescued by wild-type TDP-43, but not ALS/FTLD-associated mutants, suggesting a common TDP-43 functional deficiency in neurodegenerative diseases. Interestingly, M337V and A90V mutants also display dominant negative activities against WT TDP-43, partially explaining why M337V transgenic mice develop hippocampal degeneration similar to that in excitatory neuronal TDP-43 knockout mice, and why A90V mutation is associated with Alzheimer's disease. Further analyses reveal that a TDP-43 knockdown-induced reduction in GluN2A contributes to synaptic loss. Our results show that loss of TDP-43 function underlies hippocampal and cortical synaptic degeneration in TDP-43 proteinopathies.

Robust voltage-controlled transcutaneous energy transfer system for artificial anal sphincter.

BACKGROUND: The artificial anal sphincter (AAS) system has gained significant attention as a solution for treating fecal incontinence (FI). It relies on transcutaneous energy transfer (TET) as its primary energy source. However, changes in posture or biological tissue can cause misalignment of the coil, resulting in unstable power reception. Inadequate power affects charging efficiency, while excessive power leads to excessive heating at the receiver side. Consequently, achieving safe and constant voltage charging for the AAS becomes a complex challenge. METHODS: To maintain a consistent charging voltage and overcome the issue of variations in load and coil coupling strength, this article proposes a wireless charging control system that utilizes an LCC-S-type resonant network and phase shift to adjust the transmitting voltage based on feedback charging voltage in real time. In particular, the PI controller and neural network are introduced to change the phase-shift angle swiftly. The dynamic performance is then evaluated under different misalignments and presented with comparative results. RESULTS: The results indicate that the multilayer perceptron control system outperforms the PI. Under the complex misalignment disturbance, the average error of receiver side load voltage is only 0.007 V, with an average settling time of 960 ms. Additionally, the average temperature at the receiver side is 40.4°C. CONCLUSION: The experiments demonstrate that the proposed system effectively addresses the misalignment issue in TET during the charging, ensuring constant voltage charging at the receiver side and thermal safety.

Simulation of artificial anal sphincter motion and interaction with intestinal environment using SOFA.

BACKGROUND: Artificial anal sphincter is an implantable medical device for treating fecal incontinence. Reasonable simulation facilitates the advancement of research and reduces experiments on biological tissue. However, the device's clamping motion and sensor interaction with the intestine in the simulation still require further exploration. This article presents a simulation of the artificial anal sphincter's clamping and sensing and its interaction with the intestinal environment using the Simulation Open Framework Architecture (SOFA). METHODS: Firstly, the proposed simulation algorithm and its principles in SOFA are analyzed. Secondly, the clamping motion and sensor system of the artificial anal sphincter are simulated. Thirdly, a finite element model of intestine is established based on the properties of intestinal soft tissue. Finally, the in vitro experiments are performed. RESULTS: The simulation results indicate that the sensor system of the artificial anal sphincter has good sensing performance during the clamping motion and fecal accumulation process. Experiments have shown that optimal sensory capabilities can be achieved as the posture of the artificial anal sphincter with a roll angle between 20° and 40°. The comparison demonstrates a mean absolute error of 10%-20% between simulation and in vitro experimental results for sensor forces, which verifies the effectiveness of the simulation. CONCLUSION: The proposed novel simulation achieves a more comprehensive interaction between the artificial anal sphincter motion and intestinal environment. This study may provide more effective simulation data for guidance in improving the performance of sensor perception of artificial anal sphincter for further research.

Regulation of neuronal gene expression and survival by basal NMDA receptor activity: a role for histone deacetylase 4.

Neuronal gene expression is modulated by activity via calcium-permeable receptors such as NMDA receptors (NMDARs). While gene expression changes downstream of evoked NMDAR activity have been well studied, much less is known about gene expression changes that occur under conditions of basal neuronal activity. In mouse dissociated hippocampal neuronal cultures, we found that a broad NMDAR antagonist, AP5, induced robust gene expression changes under basal activity, but subtype-specific antagonists did not. While some of the gene expression changes are also known to be downstream of stimulated NMDAR activity, others appear specific to basal NMDAR activity. The genes altered by AP5 treatment of basal cultures were enriched for pathways related to class IIa histone deacetylases (HDACs), apoptosis, and synapse-related signaling. Specifically, AP5 altered the expression of all three class IIa HDACs that are highly expressed in the brain, HDAC4, HDAC5, and HDAC9, and also induced nuclear accumulation of HDAC4. HDAC4 knockdown abolished a subset of the gene expression changes induced by AP5, and led to neuronal death under long-term tetrodotoxin or AP5 treatment in rat hippocampal organotypic slice cultures. These data suggest that basal, but not evoked, NMDAR activity regulates gene expression in part through HDAC4, and, that HDAC4 has neuroprotective functions under conditions of low NMDAR activity.

Phosphorylation of threonine-19 of PSD-95 by GSK-3ß is required for PSD-95 mobilization and long-term depression.

Activity of glycogen synthase kinase-3ß (GSK-3ß) is required for long-term depression (LTD) via molecular mechanisms that are incompletely understood. Here, we report that PSD-95, a major scaffold protein of the postsynaptic density (PSD) that promotes synaptic strength, is phosphorylated on threonine-19 (T19) by GSK-3ß. In cultured rat hippocampal neurons, phosphorylation of T19 increases rapidly with chemical LTD and is attenuated by pharmacologic or genetic suppression of GSK-3ß. In organotypic rat hippocampal slices, we find that a nonphosphorylatable PSD-95 mutant (T19A) tagged with photoactivatable green fluorescent protein (PAGFP) shows enhanced stability in dendritic spines versus wild-type PSD-95, whereas the phosphomimetic mutant (PSD-95-T19D) is more readily dispersed. Further, overexpression of PSD-95-T19A, but not WT-PSD-95, impairs AMPA receptor internalization and the induction of LTD. These data indicate that phosphorylation on T19 by GSK-3ß destabilizes PSD-95 within the PSD and is a critical step for AMPA receptor mobilization and LTD.

Quantifying the effects of practicing a semantic task according to subclinical schizotypy.

The learning ability of individuals within the schizophrenia spectrum is crucial for their psychosocial rehabilitation. When selecting a treatment, it is thus essential to consider the impact of medications on practice effects, an important type of learning ability. To achieve this end goal, a pre-treatment test has to be developed and tested in healthy participants first. This is the aim of the current work, which takes advantage of the schizotypal traits present in these participants to preliminary assess the test's validity for use among patients. In this study, 47 healthy participants completed the Schizotypal Personality Questionnaire (SPQ) and performed a semantic categorization task twice, with a 1.5-hour gap between sessions. Practice was found to reduce reaction times (RTs) in both low- and high-SPQ scorers. Additionally, practice decreased the amplitudes of the N400 event-related brain potentials elicited by semantically matching words in low SPQ scorers only, which shows the sensitivity of the task to schizotypy. Across the two sessions, both RTs and N400 amplitudes had good test-retest reliability. This task could thus be a valuable tool. Ongoing studies are currently evaluating the impact of fully deceptive placebos and of real antipsychotic medications on these practice effects. This round of research should subsequently assist psychiatrists in making informed decisions about selecting the most suitable medication for the psychosocial rehabilitation of a patient.

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.

GluN2A mediates ketamine-induced rapid antidepressant-like responses.

Ketamine was thought to induce rapid antidepressant responses by inhibiting GluN2B-containing N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), which presents a promising opportunity to develop better antidepressants. However, adverse side effects limit the broader application of ketamine and GluN2B inhibitors are yet to be approved for clinical use. It is unclear whether ketamine acts solely through GluN2B-dependent mechanisms. The present study reports that the loss of another major NMDAR subunit, GluN2A, in adult mouse brains elicits robust antidepressant-like responses with limited impact on the behaviors that mimic the psychomimetic effects of ketamine. The antidepressant-like behavioral effects of broad NMDAR channel blockers, such as ketamine and MK-801 (dizocilpine), were mediated by the suppression of GluN2A, but not by the inhibition of GluN2B. Moreover, treatment with ketamine or MK-801 rapidly increased the intrinsic excitability of hippocampal principal neurons through GluN2A, but not GluN2B. Together, these findings indicate that GluN2A mediates ketamine-triggered rapid antidepressant-like responses.

C57BL/6J and C57BL/6N mice exhibit different neuro-behaviors and sensitivity to midazolam- and propofol-induced anesthesia.

Phenotypes of inbred mice are strain-dependent, indicating the important influence of genetic background in biomedical research. C57BL/6 is one of the most commonly used inbred mouse strains, and its two closely related substrains, C57BL/6J and C57BL/6N, have been separated for only about 70 years. These two substrains have accumulated genetic variations and exhibit different phenotypes, but it remains unclear whether they respond to anesthetics differently. In this study, commercially acquired wildtype C57BL/6J or C57BL/6N mice from two different sources were analyzed and compared for their response to a spectrum of anesthetics (midazolam, propofol, esketamine or isoflurane anesthesia) and their performance in a series of behavioral tests associated with neurological functions including open field test (OFT), elevated plus maze (EPM), Y maze, prepulse inhibition (PPI), tail strain test (TST) and forced swimming test (FST). Loss of the righting reflex (LORR) is used to measure the anesthetic effects. Our results suggested that the anesthesia induction time induced by either of the four anesthetics were comparable for the C57BL/6J and C57BL/6N mice. However, C57BL/6J or C57BL/6N mice do exhibit different sensitivity to midazolam and propofol. The anesthesia duration of midazolam of C57BL/6J mice was about 60% shorter than that of the C57BL/6N mice, while the LORR duration induced by propofol in C57BL/6J mice was 51% longer than that of the C57BL/6N. In comparison, the two substrains were anesthetized by esketamine or isoflurane similarly. In the behavioral analysis, the C57BL/6J mice exhibited a lower level of anxiety- and depression-like behaviors in OFT, EPM, FST and TST than the C57BL/6N mice. Locomotor activity and sensorimotor gating of these two substrains remained comparable. Our results stress the point that when selecting inbred mice for allele mutation or behavioral testing, the influence of even subtle differences in genetic background should be fully considered.

Esketamine Anesthetizes Mice With a Similar Potency to Racemic Ketamine.

Esketamine, the right-handed optical isomer of racemic ketamine, has recently become widely used for anesthesia and analgesia as a replacement for racemic ketamine. However, there are limited studies comparing the anesthetic and analgesic effects of esketamine and racemic ketamine in mice. This research was conducted to analyze the dose-dependent anesthetic and analgesic efficacy of esketamine in mice and to compare its potency with that of the racemate. We tested the anesthetic effects of different doses of esketamine and compared its potency with that of the racemate using righting reflex tests. Then, the acetic acid-induced pain model and formalin-induced pain model were used to investigate the analgesic effect. Compared with racemic ketamine, an equivalent dose of esketamine at 100 mg/kg was required to induce stable anesthesia. In contrast, 5 mg/kg esketamine was sufficient to provide analgesic effects similar to those of 10 mg/kg ketamine. Together, esketamine had a similar potency to racemic ketamine for anesthesia and a stronger potency for analgesia in mice.

Flexible PTh/GQDs/TiO2 composite with superior visible-light photocatalytic properties for rapid degradation pollutants.

Flexible fiber membranes for pollutant removal have received increasing attention due to their high adsorption performance and easy recycling characteristics. However, due to the lack of environmentally friendly regeneration, some adsorption membranes have low regeneration efficiency, especially in terms of chemical adsorption, so they lack reusability. This study prepares a series of conducting polymer [PAn (polyaniline) or PPy (polypyrrole) or PTh (polythiophene)] graphene quantum dots (GQDs, the size of GQDs is about 20 nm)/TiO2 ternary fiber membranes via a facile electrospinning method with chemical deposition. Remarkably, this creates an anatase TiO2 and π-conjugated system. The combination is beneficial to the photocatalytic degradation of organic pollutants, showing synergistic promotion in both the degradation rate and the degree of decomposition. The UV-vis test shows that the combination of GQDs broadens the optical response threshold of TiO2, from near ultraviolet region excitation to visible region excitation. At the same time, the conductive polymer load further reduces the energy required for photogenerated electron transfer, which theoretically improves the degradation effect. Photocatalytic degradation tests showed that the PTh/GQDs/TiO2 fiber membrane exhibited significant high photocatalytic activity of visible-light in the methylene blue (MB) and TC degradation. The degradation rate level is 92.90% and 80.58%, respectively and the MB removal is more than 4 times that of bare TiO2 membrane. After photocatalytic regeneration four times, the regeneration efficiency can be maintained above 95%. Notably, various experimental results show that the interface charge transfer mechanism between GQDs/TiO2 and PTh follows the Z-scheme heterojunction, which maximizes the retention of strong reducing electrons and oxidation holes. In the degradation, the active species of ·O2 - and ·OH, make different contributions in the photocatalysts, which oxidize and break down the pollutant molecules into small molecules and then to harmless substances. According to the electronegativity difference of the material itself, PTh acts as electron acceptor in the degradation system, and TiO2 fiber membrane doped with GQDs acts as electron donor. The present research, not only offers feasibility of the PTh/GQDs/TiO2 flexible fiber membrane as an environment-friendly catalyst, but also motivates researchers to develop flexible fiber materials for future photocatalytic technology.

Synergistic Effects of Magnetic Z-Scheme g-C3N4/CoFe2O4 Nanofibres with Controllable Morphology on Photocatalytic Activity.

The rational design of interfacial contacts plays a decisive role in improving interfacial carrier transfer and separation in heterojunction photocatalysts. In Z-scheme photocatalysts, the recombination of photogenerated electron-hole pairs is prevented so that the redox capacity is maintained. Here, one-dimensional graphitic carbon nitride (g-C3N4)/CoFe2O4 fibres were synthesised as a new type of magnetic Z-scheme visible-light photocatalyst. Compared with pure g-C3N4 and CoFe2O4, the prepared composite photocatalysts showed considerably improved performance for the photooxidative degradation of tetracycline and methylene blue. In particular, the photodegradation efficiency of the g-C3N4/CoFe2O4 fibres for methylene blue was approximately two and seven times those of g-C3N4 and CoFe2O4, respectively. The formation mechanism of the Z-scheme heterojunctions in the g-C3N4/CoFe2O4 fibres was investigated using photocurrent spectroscopy and electrochemical impedance spectroscopy. We proposed that one of the reasons for the improved photodegradation performance is that the charge transport path in one-dimensional materials enables efficient photoelectron and hole transfer. Furthermore, the internal electric field of the prepared Z-scheme photocatalyst enhanced visible-light absorption, which provided a barrier for photoelectron-hole pair recombination.

Differential and substrate-specific inhibition of γ-secretase by the C-terminal region of ApoE2, ApoE3, and ApoE4.

Aberrant low γ-secretase activity is associated with most of the presenilin mutations that underlie familial Alzheimer's disease (fAD). However, the role of γ-secretase in the more prevalent sporadic AD (sAD) remains unaddressed. Here, we report that human apolipoprotein E (ApoE), the most important genetic risk factor of sAD, interacts with γ-secretase and inhibits it with substrate specificity in cell-autonomous manners through its conserved C-terminal region (CT). This ApoE CT-mediated inhibitory activity is differentially compromised in different ApoE isoforms, resulting in an ApoE2 > ApoE3 > ApoE4 potency rank order inversely correlating to their associated AD risk. Interestingly, in an AD mouse model, neuronal ApoE CT migrates to amyloid plaques in the subiculum from other regions and alleviates the plaque burden. Together, our data reveal a hidden role of ApoE as a γ-secretase inhibitor with substrate specificity and suggest that this precision γ-inhibition by ApoE may protect against the risk of sAD.

NMDA receptor-dependent prostaglandin-endoperoxide synthase 2 induction in neurons promotes glial proliferation during brain development and injury.

Astrocytes play critical roles in brain development and disease, but the mechanisms that regulate astrocyte proliferation are poorly understood. We report that astrocyte proliferation is bi-directionally regulated by neuronal activity via NMDA receptor (NMDAR) signaling in neurons. Prolonged treatment with an NMDAR antagonist reduced expression of cell-cycle-related genes in astrocytes in hippocampal cultures and suppressed astrocyte proliferation in vitro and in vivo, whereas neuronal activation promoted astrocyte proliferation, dependent on neuronal NMDARs. Expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) is induced specifically in neurons by NMDAR activation and is required for activity-dependent astrocyte proliferation through its product, prostaglandin E2 (PGE2). NMDAR inhibition or Ptgs2 genetic ablation in mice reduced the proliferation of astrocytes and microglia induced by mild traumatic brain injury in the absence of secondary excitotoxicity-induced neuronal death. Our study defines an NMDAR-mediated signaling mechanism that allows trans-cellular control of glial proliferation by neurons in brain development and injury.

CHMP2B regulates TDP-43 phosphorylation and cytotoxicity independent of autophagy via CK1.

The ESCRT protein CHMP2B and the RNA-binding protein TDP-43 are both associated with ALS and FTD. The pathogenicity of CHMP2B has mainly been considered a consequence of autophagy-endolysosomal dysfunction, whereas protein inclusions containing phosphorylated TDP-43 are a pathological hallmark of ALS and FTD. Intriguingly, TDP-43 pathology has not been associated with the FTD-causing CHMP2BIntron5 mutation. In this study, we identify CHMP2B as a modifier of TDP-43-mediated neurodegeneration in a Drosophila screen. Down-regulation of CHMP2B reduces TDP-43 phosphorylation and toxicity in flies and mammalian cells. Surprisingly, although CHMP2BIntron5 causes dramatic autophagy dysfunction, disturbance of autophagy does not alter TDP-43 phosphorylation levels. Instead, we find that inhibition of CK1, but not TTBK1/2 (all of which are kinases phosphorylating TDP-43), abolishes the modifying effect of CHMP2B on TDP-43 phosphorylation. Finally, we uncover that CHMP2B modulates CK1 protein levels by negatively regulating ubiquitination and the proteasome-mediated turnover of CK1. Together, our findings propose an autophagy-independent role and mechanism of CHMP2B in regulating CK1 abundance and TDP-43 phosphorylation.

Potent mGluR5 antagonists: pyridyl and thiazolyl-ethynyl-3,5-disubstituted-phenyl series.

We report the synthesis of four series of 3,5-disubstituted-phenyl ligands targeting the metabotropic glutamate receptor subtype 5: (2-methylthiazol-4-yl)ethynyl (1a-j,), (6-methylpyridin-2-yl)ethynyl (2a-j), (5-methylpyridin-2-yl)ethynyl (3a-j,), and (pyridin-2-yl)ethynyl (4a-j,). The compounds were evaluated for antagonism of glutamate-mediated mobilization of internal calcium in an mGluR5 in vitro assay. All compounds were found to be full antagonists and exhibited low nanomolar to subnanomolar activity.

Fear can be more harmful than the severe acute respiratory syndrome coronavirus 2 in controlling the corona virus disease 2019 epidemic.

The current corona virus disease 2019 outbreak caused by severe acute respiratory syndrome coronavirus 2 started in Wuhan, China in December 2019 and has put the world on alert. To safeguard Chinese citizens and to strengthen global health security, China has made great efforts to control the epidemic. Many in the global community have joined China to limit the epidemic. However, discrimination and prejudice driven by fear or misinformation have been flowing globally, superseding evidence and jeopardizing the anti-severe acute respiratory syndrome coronavirus 2 efforts. We analyze this phenomenon and its underlying causes and suggest practical solutions.

Stability and infectivity of coronaviruses in inanimate environments.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious virus that can transmit through respiratory droplets, aerosols, or contacts. Frequent touching of contaminated surfaces in public areas is therefore a potential route of SARS-CoV-2 transmission. The inanimate surfaces have often been described as a source of nosocomial infections. However, summaries on the transmissibility of coronaviruses from contaminated surfaces to induce the coronavirus disease 2019 are rare at present. This review aims to summarize data on the persistence of different coronaviruses on inanimate surfaces. The literature was systematically searched on Medline without language restrictions. All reports with experimental evidence on the duration persistence of coronaviruses on any type of surface were included. Most viruses from the respiratory tract, such as coronaviruses, influenza, SARS-CoV, or rhinovirus, can persist on surfaces for a few days. Persistence time on inanimate surfaces varied from minutes to up to one month, depending on the environmental conditions. SARS-CoV-2 can be sustained in air in closed unventilated buses for at least 30 min without losing infectivity. The most common coronaviruses may well survive or persist on surfaces for up to one month. Viruses in respiratory or fecal specimens can maintain infectivity for quite a long time at room temperature. Absorbent materials like cotton are safer than unabsorbent materials for protection from virus infection. The risk of transmission via touching contaminated paper is low. Preventive strategies such as washing hands and wearing masks are critical to the control of coronavirus disease 2019.

GluN2A-selective positive allosteric modulator-nalmefene-flumazenil reverses ketamine-fentanyl-dexmedetomidine-induced anesthesia and analgesia in rats.

Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments.