Search Results (95)

Epidemiological investigations have indicated that females are particularly susceptible to perfluorooctane sulfonate (PFOS)-induced cognitive impairment, yet the mechanisms underlying this sex-specific vulnerability remain obscure. Estrogen and estrogen receptor β (ERβ) signaling are essential for female brain function, but their role in PFOS-induced neurotoxicity has not been explored. We therefore hypothesized that disruption of astrocyte-derived estrogen–ERβ signaling, leading to downregulation of N-myc downstream-regulated gene 2 (NDRG2) and subsequent synaptic dysfunction, contributes to PFOS-induced neurotoxicity in females. Female rats were exposed to PFOS for 30 days, followed by behavioral tests and hippocampal analysis. PC12 cells were treated with astrocyte-conditioned medium (ACM) to assess synaptic injury. Molecular docking was further performed to predict the binding affinity between PFOS and ERβ. In vivo, PFOS exposure impaired cognitive performance and caused hippocampal dysfunction, accompanied by decreased levels of estradiol (E2), aromatase (AROM), ERβ, N-myc downstream regulated gene 2 (NDRG2), and AMPA receptors (AMPARs), together with increased glial fibrillary acidic protein (GFAP) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus. In vitro, PFOS-exposed C6 cells showed reduced E2, AROM, ERβ, and NDRG2, along with elevated GFAP and extracellular glutamate concentration. PC12 cells treated with PFOS-ACM exhibited decreased synaptophysin (SYP), postsynaptic density protein 95 (PSD-95), and AMPARs, as well as increased CaMKII, indicative of synaptic injury. Pretreatment with E2 or the ERβ agonist diarylpropionitrile (DPN) could reverse these molecular alterations and mitigate neuronal dysfunction. Molecular docking revealed a strong binding affinity between PFOS and ERβ. Collectively, these findings support our hypothesis that PFOS impairs cognitive function in female rats by disrupting astrocyte-derived estrogen–ERβ–NDRG2 signaling, with NDRG2 as a potential downstream effector. This provides a mechanistic basis for the heightened female susceptibility to PFOS neurotoxicity and highlighting ERβ as a potential therapeutic target. Full article

The present investigation was designed to assess how perinatal contact with the pyrethroid insecticide cyfluthrin (CY) influences cognitive performance in developing rat progeny and to clarify the contributing cellular events through examination of neuroinflammatory processes alongside pyroptotic and apoptotic pathways. An experimental framework involving CY administration during gestation was implemented using Sprague–Dawley (SD) dams, with subsequent monitoring of placental parameters and neonatal outcomes. Once offspring reached postnatal day twenty-one, their behavior was characterized via a battery consisting of the open field paradigm, novel object recognition task, and the Morris water navigation test. Hippocampal tissue architecture and fine structural details were visualized by employing hematoxylin–eosin (HE) staining and Nissl substance labeling. Protein and transcript abundances for pro-inflammatory mediators (TNF-α, IL-6), synaptic constituents (postsynaptic density protein-95, PSD-95; synaptophysin, SYP), and pyroptotic machinery components (NLRP3, GSDMD, Caspase-1) within hippocampal homogenates were quantified through immunoblotting and real-time quantitative PCR procedures, and the spatial distribution of these molecules was validated via immunohistochemical detection. Neuronal apoptosis was assessed by TUNEL staining. The results demonstrated that gestational CY exposure led to reduced placental weight and diameter, decreased blood sinus area in the labyrinth zone, lower offspring birth weight, and impaired catch-up growth. Behavioral tests revealed that CY-exposed offspring exhibited diminished spontaneous locomotor activity, impaired novel object recognition memory, and significant deficits in spatial learning and memory. Pathological analysis showed disorganized neuronal arrangement and reduced Nissl bodies in the hippocampal CA1 region. Compared to the control group, CY exposure markedly upregulated the protein expression of TNF-α and IL-6, downregulated PSD-95 and SYP, activated the NLRP3/GSDMD/Caspase-1-mediated pyroptotic pathway, and increased the expression of the apoptotic protein Caspase-3, culminating in a significant increase in hippocampal neuronal apoptosis. In conclusion, early-life exposure to cyfluthrin impairs cognitive function in offspring, an effect closely associated with the induction of hippocampal neuroinflammation and the activation of pyroptotic and apoptotic pathways. These findings provide novel toxicological evidence for a more comprehensive assessment of the potential health risks posed by CY exposure in human populations. Full article

Primary neuronal cultures from the brain are critical for investigating disease-specific cellular and molecular mechanisms in mouse models. Current methods for obtaining primary cultures require embryonic brains that are affected by embryonic lethality and genotypic characterization in severe disease models such as sickle cell disease (SCD). Furthermore, these neuronal cultures require about 14 days in vitro (DIVs) for neurite outgrowth to mature. We adapted and optimized a relatively simplified and reproducible method using brains from postnatal day 1 mouse pups for isolating and culturing hippocampal and cortical neurons. This approach produces viable neurons that attach, extend neurites, and express key synaptic markers by 7 DIV and also minimizes glial outgrowth. We successfully applied this approach to isolating and culturing hippocampal and cortical neurons from the brains of one-day-old (P1) pups of humanized transgenic homozygous BERK sickle cell and control mice. Morphological observations at 3, 7, and 14 DIVs demonstrated robust neuronal attachment, neurite outgrowth, and overall structural development in both male and female hippocampal and cortical neurons. Neurons in culture expressed key markers including neuronal nuclear protein (NeuN/Rbfox3), neurofilament 200 (NF200), microtubule-associated protein 2 (MAP2), vesicular glutamate transporter 1 (VGLUT1), postsynaptic density protein 95 (PSD 95), and glutamate N-methyl-D-aspartate receptor subunit 2B (GluN2B). Notably, male SCD hippocampal neurons evinced a higher density of PSD 95 puncta on dendritic spines compared to controls on 7 as well as 14 DIVs. Incubation of male hippocampal neurons in a sickle cell-like microenvironment with TNF-α and heme further increased the density of PSD 95 puncta and colocalization of GluN2B with PSD 95, supporting the utility of this culture system for examining disease-relevant structural and molecular responses. This optimized culture system provides a simplified and reproducible platform to investigate the mechanisms involving neuronal dysfunction in challenging mouse models of brain disorders. Full article

Cognitive impairment induced by a high-fat high-fructose diet (HFFD) is associated with gut–liver–brain axis dysfunction, yet whether polysaccharide intervention can modulate this axis to achieve cognitive rescue remains unexplored. This study investigated whether Elaeagnus angustifolia polysaccharide (EAP) is associated with protection against HFFD-induced cognitive decline by modulating this axis. Male C57BL/6J mice (n = 15/group) received Control, HFFD, HFFD + LEAP (300 mg/kg/day EAP), or HFFD + HEAP (800 mg/kg/day EAP) for 14 weeks. HEAP improved spatial memory, reducing escape latency by 31.2% on day 5 (p < 0.01). Multi-omics and histopathological analyses revealed that EAP was dose-dependently associated with restructuring of the gut microbiota, expanding Muribaculaceae and other SCFA-producers while suppressing pathobionts, thereby reversing the Firmicutes/Bacteroidota ratio from 1.71 to 0.94 (p < 0.01). Elevated cecal, hepatic, and cerebral acetate, propionate, and butyrate (p < 0.01) were associated with improved intestinal barrier integrity, attenuated systemic LPS translocation, and reduced hepatic inflammation and changes consistent with normalization toward control levels of PPARα/γ signaling. These peripheral improvements were accompanied by changes in the hippocampus, where EAP suppressed IBA-1 microglial activation (from 4.5-fold to 2.1-fold of control, p < 0.01) and IL-6/TNF-α signaling, changes in neurotransmitter balance (Glu, 5-HT, DA), and preserved postsynaptic density ultrastructure and PSD-95 expression (p < 0.01). These findings support a role for EAP in modulating the gut–liver–brain axis and may help prevent diet-related cognitive impairment, supporting its development as a microbiome-targeted functional food ingredient. Full article

Maternal infection (MI) can increase the risk of neurodevelopmental and behavioural changes. This study examined MI-induced changes in motor coordination through the inflammatory-pathway-mediated epigenetic status of Reln. On gestational day (GD) 10, rats were assigned as (i) Control (Ctrl); (ii) Cronobacter sakazakii (CS) infection on GD-10 through recto-vaginal colonization; (iii) Negative Control (NC) [infected with C. sakazakii and treated with dimethyl sulfoxide (DMSO) 1 h before and 24 h after infection]; and (iv) C. sakazakii-infected rats treated with matrix metalloproteinase inhibitor (MMPI), 1 h before and 24 h after infection (CS + MMPI). Offspring were subjected to footprint analysis and the ladder rung walking test, which revealed that MI caused significant deficits in motor coordination. In addition, MI activated complement components—a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1, C5a)—as well as proinflammatory cytokines such as interleukin-6 (IL-6) and matrix metalloproteinases (MMP-2, MMP-3, and MMP-9). Furthermore, the levels of DNA methyltransferase 3 alpha (DNMT3A), methyl-CpG-binding protein 2 (MeCP2), and histone H3 lysine 4 trimethylation (H3K4me3) were elevated in the CS and NC groups. Concurrently, the level of Reln promoter methylation increased; as a result, mRNA and protein, as well as postsynaptic density protein-95 (PSD-95), levels were decreased. Overall, the findings suggest that MI altered MMP-2/3/9 activity, H3K4me3, and the methylation of Reln, thereby affecting reelin, synaptic protein expression, and motor coordination in an experimental meningitis rat model. Full article

Traumatic brain injury (TBI) can lead to persistent adverse outcomes, including cognitive and emotional dysfunction, with recent estimates indicating that up to 50% of individuals with mild TBI experience long-term symptoms. Growing evidence suggests that biological sex influences TBI outcomes and recovery trajectories; however, the molecular underpinnings driving these sex-specific differences remain poorly understood. In this study, a preclinical TBI model was used to directly compare chronic glutamatergic alterations in adult male and female Sprague Dawley rats. To define frontocortical molecular signatures associated with sex-specific glutamatergic dysfunction, proteomic analyses were conducted. Proteomic data revealed dysregulation of key pathways, cellular processes, and molecular regulators involved in excitatory signaling and synaptic function in both sexes. Biomarker profiling identified a single common biomarker between males and females, along with multiple biomarkers unique to each sex. Furthermore, two key brain regions highly susceptible to TBI, the prefrontal cortex and hippocampal subregions, were examined for chronic alterations in key glutamatergic signaling proteins, including N-methyl-D-aspartate (NMDA) receptors and the excitatory synaptic marker postsynaptic density protein 95 (PSD95). Immunofluorescence analyses revealed both sex- and region-specific alterations in the expression of NMDA receptor subunits, as well as in PSD95. Notably, many of these changes were concentrated within the hippocampal subregions, suggesting long-term dysregulation of hippocampal glutamatergic circuitry following injury. Together, these findings indicate the emergence of chronic sex-specific pathophysiology in glutamate signaling after TBI and highlight the importance of incorporating sex as a biological variable in the development of precision medicine-based therapeutic strategies for TBI. Full article

Background: Prenatal cannabinoid exposure (PCE) causes neurodevelopmental impairments affecting learning and memory; however, the receptor-level interactions underlying these cognitive deficits remain poorly understood. This study investigated whether a moderate dose of prenatal Δ⁹-tetrahydrocannabinol (THC) exposure alters the biophysical properties of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are critical mediators of excitatory neurotransmission and synaptic plasticity. Methods: Pregnant Sprague-Dawley rats received a moderate dose (5 mg/kg) of THC or vehicle control via oral gavage throughout gestation and early postnatal development. Single-channel electrophysiological activity of the AMPA receptors (AMPARs) was recorded using patch-clamp techniques on synaptosomal AMPARs reconstituted into artificial lipid bilayers from adolescent offspring. Western blot analysis of GluA1- and GluA2-containing AMPAR subunits and the postsynaptic scaffold protein postsynaptic density 95 (PSD95) was conducted to assess protein levels. Results: Prenatal THC exposure decreased AMPAR open-channel probability, reduced mean open time, increased mean closed time, and altered burst channel activity significantly, without altering GluA1, GluA2, or PSD95 protein levels. Furthermore, the interactive channel-gating activity observed in control synaptosomes was absent in synaptosomes derived from THC-exposed offspring. Conclusions: Prenatal cannabinoid exposure induces early alterations in glutamatergic synaptic function primarily mediated by changes in AMPAR channel kinetics rather than receptor abundance. By identifying AMPAR single-channel dysfunction as a sensitive marker of PCE-induced synaptic disruption, this work provides a mechanistic framework linking prenatal THC exposure to long-term alterations in learning and memory. Full article

Glutamate metabotropic receptors (mGluRs) and their molecular partners at the postsynaptic density (PSD) represent a highly dynamic molecular hub that integrates multiple neurotransmitter signals and regulates synaptic plasticity and metaplasticity, which are putatively involved in the pathophysiology of psychiatric illnesses, including schizophrenia. Group I mGluRs (mGluR1 and mGluR5) interact with PSD adaptor and scaffolding proteins, such as Homer, Shank, Norbin, and PICK1, as well as intracellular downstream effectors, creating a molecular network that resembles a Lego-like structure, where modular protein interactions fine-tune glutamatergic transmission. Evidence from preclinical research indicates that dysregulation of mGluR expression and function, along with disrupted PSD protein expression, may contribute to the pathophysiology of schizophrenia by altering glutamatergic neurotransmission and synaptic stability. Antipsychotic mechanisms of action may involve, at least in part, the modulation of mGluR activity mediated through PSD proteins. Notably, novel agents that enhance spinogenesis by acting at the level of PSD proteins, such as SPG302, may open promising avenues for therapeutics aimed at restoring synaptic integrity. While Group I mGluRs dominate postsynaptic regulation, Group II (mGluR2/3) and III (mGluR4/6/7/8) receptors -primarily presynaptic- inhibit neurotransmitter release and plasticity, offering complementary therapeutic avenues. Emerging strategies, such as allosteric modulators of mGluRs, aim to rebalance synaptic signaling in treatment-resistant schizophrenia. This review synthesizes how PSD proteins and mGluRs interact in schizophrenia, exploring their potential as druggable targets for novel therapies. Full article

The efficacy of stigmasterol (STG) has not been previously evaluated in post-traumatic stress disorder (PTSD) models. Mice exposed to single prolonged stress with foot shock (SPS + FS) received oral STG (25 or 50 mg/kg) for 14 days. Serum corticosterone and serotonin levels were measured, anxiety and cognition were assessed, synaptic plasticity-related proteins and genes were quantified, and neuronal nitric oxide synthase (nNOS), nitric oxide (NO) accumulation, nNOS-postsynaptic density protein 95 (PSD95), and nNOS-carboxy-terminal PDZ ligand of nNOS (CAPON) interactions were evaluated. STG significantly reduced serum corticosterone levels and increased serotonin levels altered by SPS+FS exposure. Behavioral analyses revealed attenuation of anxiety-like behavior and cognitive deficits. STG increased hippocampal synaptic plasticity-related proteins and genes and increased the number and maturation of doublecortin⁺ cells. Additionally, STG suppressed the PTSD-induced nNOS overactivation and NO accumulation in the hippocampus and serum, and altered nNOS-PSD95 and nNOS-CAPON associations in the hippocampus. Together, these findings provide integrated in vivo evidence suggesting that STG may influence stress-related neurobiological pathways relevant to PTSD. Full article

This study sought to evaluate the neuroprotective effects of YGD in an oxidative stress-induced Alzheimer’s disease (AD)-like cellular model and to elucidate the underlying molecular pathways, with a focus on tau phosphorylation, Aβ accumulation, and antioxidant defense mechanisms. Rat primary hippocampal neurons were exposed to hydrogen peroxide to induce oxidative stress. The effects of YGD on neuronal viability, neurite outgrowth, and synaptic integrity were assessed using the immunodetection of microtubule-associated protein 2 (MAP2), postsynaptic density protein 95 (PSD-95), and synapsin-1. Levels of phosphorylated tau and Aβ were quantified, and the involvement of extracellular signal-regulated kinase (ERK), glycogen synthase kinase 3β (GSK3β), and nuclear factor-erythroid 2-related factor-2 (Nrf2) pathways was examined. Additionally, in silico molecular docking studies targeting the ATP-binding site of GSK3β were conducted to screen major phytochemicals from the ten medicinal herbs constituting YGD. YGD markedly enhanced neuronal viability under oxidative stress, promoted neurite extension, and increased synaptic marker expression (MAP2, PSD-95, and synapsin-1). Treatment reduced phosphorylated tau by suppressing ERK and GSK3β activation and significantly decreased Aβ accumulation. YGD also upregulated antioxidant defenses via the activation of the Nrf2 pathway. Docking simulations identified oleanolic acid (from Cornus officinalis) as the most potent GSK3β binder (−9.86 ± 0.40 kcal/mol), forming stable interactions with ARG96, ASN95, and GLU97. Additional compounds, including alisol C, drypemolundein B, and friedelin, demonstrated favorable binding energies and engaged key ATP-binding site residues. YGD confers neuroprotection through the integrated modulation of tau phosphorylation, Aβ pathology, and oxidative stress, partly via the multi-target engagement of GSK3β by its constituent phytochemicals. These findings support that YGD attenuates oxidative stress-induced AD-like cellular alterations. Full article

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders. Full article

Neurodegenerative diseases (NDs) have emerged as a significant global health crisis, disproportionately affecting the aging population. As longevity increases, the incidence, healthcare costs, and caregiver burden associated with NDs are escalating at an alarming rate. As of recent data, NDs such as Alzheimer’s disease (AD) are not only significant health burdens but also reflect a complex interplay between socio-economic factors and healthcare systems worldwide. Gac fruit (Momordica cochinchinensis) is a rich source of bioactive compounds that has been used as food and traditional medicine. Gac fruit ameliorates memory deficits, enhances beta amyloid (Aβ)_1–42 clearance, and induces neurite outgrowth. In this study, we examined the anti-neurodegenerative and synaptic improvement effect of fresh gac fruit parts extracts (FGPEs) produced from different solvents. Results showed that the 80% ethanol extract of peel (PE-EtOH) and ethyl acetate extract of seed (SE-EtOAc) significantly protected HT-22 cells by attenuating Aβ-induced cell death, intracellular reactive oxygen species (ROS) production, mitochondrial dysfunction, and synaptic dysfunction. PE-EtOH protected synaptic functions by significantly increasing the postsynaptic density protein-95 (PSD-95) and reducing the neurexin 2 mRNA expression. In contrast, SE-EtOAc increased the PSD-95 and neurexin 3 and reduced the neurexin 2 expressions. These findings indicate that PE-EtOH and SE-EtOAc could have great potential in ameliorating Aβ-induced toxicity in an HT-22 cell model. Full article

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder. Full article

Background: Sleep deprivation (SD) is a common condition affecting many people in modern life. Edaravone (Eda) is a neuroprotective drug, but whether it can improve cognitive impairment caused by SD remains unclear. Methods: Animals received oral gavage doses of Eda (10, 20, and 40 mg/kg) for 8 and 5 days before and during SD. Starting from the 6th day, a modified multiple platform model was used to produce SD in mice for 72 h. The Lashley III maze was used for evaluating spatial learning and memory. Malondialdehyde (MDA) in the hippocampus and serum corticosterone were assessed. Total antioxidant capacity (TAC) and the activity of the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Growth-associated protein 43 (GAP-43), synapsin 1 (SYN-1), post-synaptic density-95 (PSD-95), synaptophysin (SYP), and signs of inflammation were detected using Western blotting. Results: SD caused cognitive impairment, whereas Eda pretreatment warded off such an effect. While serum corticosterone levels rose with SD as well, they decreased in SD mice that received Eda (p < 0.05). Moreover, Eda normalized the SD-induced decline in hippocampal activity of SOD and GPx, lowered MDA levels, and elevated TAC (p < 0.01). Additionally, the hippocampal levels of GAP-34, SYP, SYN-I, and PSD-95 were elevated, while IL-1β and tumor necrosis factor α (TNF-α) were lowered following Eda pretreatment (p < 0.05). Conclusions: SD caused memory impairment; however, pretreatment with Eda improved memory by upregulating synaptic proteins in the hippocampus and having anti-inflammatory and antioxidant effects. Full article

Background: Terahertz (THz) waves, lying between millimeter waves and infrared light, may interact with biomolecules due to their unique energy characteristics. However, whether THz waves are neurally regulated remains controversial, and the underlying mechanism is elusive. Methods: Mouse brain slices were exposed to 1.94 THz waves for 1 h. Synaptic plasticity was evaluated via transmission electron microscopy (TEM), long-term potentiation (LTP), and neuronal class III β-tubulin (Tuj1) and synaptophysin (SYN) expression. Immunofluorescence (IF) and electrophysiology were used to identify neurons sensitive to THz waves. The calcium activity of excitatory neurons, glutamate receptor currents, and glutamate neuron marker expression was also assessed using calcium imaging, a patch clamp, and Western blotting (WB). Optogenetics and chemogenetics were used to determine the role of excitatory neurons in synaptic plasticity impairment after THz wave exposure. NMDA receptor 2B (GluN2B) was overexpressed in the ventral hippocampal CA1 (vCA1) by a lentivirus to clarify the role of GluN2B in THz wave-induced synaptic plasticity impairment. Results: Exposure to 1.94 THz waves increased postsynaptic density (PSD) thickness and reduced the field excitatory postsynaptic potential (fEPSP) slope and Tuj1 and SYN expression. THz waves diminished vCA1 glutamatergic neuron activity and excitability, neural electrical activity, and glutamate transporter function. THz waves reduced N-methyl-D-aspartate receptor (NMDAR) current amplitudes and NMDAR subunit expression. Activating vCA1 glutamatergic neurons through optogenetics and chemogenetics mitigated THz wave-induced synaptic plasticity impairment. GluN2B subunit overexpression improved synaptic plasticity marker expression, synaptic ultrastructure, and the fEPSP slope. Conclusions: Exposure to 1.94 THz waves decreased synaptic plasticity, glutamatergic neuron excitability, and glutamatergic synaptic transmission in the vCA1. Glutamatergic neuron activation and GluN2B overexpression alleviated THz wave-induced synaptic plasticity impairment; thus, neuromodulation could be a promising therapeutic strategy to mitigate the adverse effects of THz radiation. Full article