Spatial Memory Research Articles

Aging leads to various changes in nervous system functions. Older humans and animals exhibit altered movement patterns and experience alterations in memory and motor functions. Rodent models, particularly aged C57BL/6 mice, have been instrumental in studying behavioral and neurophysiological changes associated with aging. This study aimed to characterize age-related cognitive and motor decline and examine its association with molecular changes in a physiologically aged murine model. For this purpose, female C57BL/6Cenp mice aged 2, 20, and 26 months were used. Several behavioral tests were conducted to evaluate motor and cognitive functions. Additionally, gene expression levels were analyzed in prefrontal cortex and hippocampus samples. Twenty-month-old mice exhibited reduced muscle strength, altered gait patterns, impaired balance on the rotarod test, and deficits in spatial reference memory as assessed by the Barnes maze. Motor function further deteriorated in senescent mice (26-month-old), accompanied by spatial memory impairment as assessed using forced Y-maze test. Moreover, significant changes were observed in the expression of genes associated with synaptic plasticity (ARC, CREB1), neuronal activity (FOS), myelination (OLIG1, MAL), and oxidative stress (CYBA, CYBB, NCF1). These findings confirm that aging is a complex phenomenon marked by progressive cognitive and motor impairments, driven by molecular changes in brain regions involved in critical functions such as motor processes and cognition.

Long noncoding RNA FTX regulates lead-induced synaptic vesicle damage in a miR-20b-5p/SNAP25 dependent axis.

Mahjong, a traditional Chinese tile-based game, has been widely reported to be closely associated with better cognitive function. However, its effects on the cognitive function of patients with schizophrenia have not yet been studied. In a pilot study, 49 patients diagnosed with schizophrenia were randomly assigned to the intervention group (Mahjong combined with standard treatment) and the control group (standard treatment). The intervention group engaged in cognitive training through Mahjong for 2h per day, 4 days per week for 12 weeks. Primary cognitive outcomes were assessed using Cambridge Neuropsychological Test Automated Battery (CANTAB), while secondary outcomes include quality of life, clinical symptoms, anhedonia, treat side effects, and personal and social functioning. Assessments were conducted at baseline (T0), the 4th week (T1), the 8th week (T2), and the 12th week (T3). The intervention group exhibited progressive improvements in both reaction time and movement time throughout the study. No significant differences were found between the intervention and control groups regarding visual memory, novel learning, strategy utilization, spatial memory performance or complex visual task accuracy. The intervention group demonstrated gradual improvements in quality of life, whereas no significant changes were noted in other secondary outcomes. While this exploratory study suggests that Mahjong intervention may benefit certain cognitive functions and quality of life in patients with schizophrenia, these findings should be interpreted with caution. Further research with larger, more diverse samples and longer intervention is necessary to confirm and extend these findings. The trial is registered with https://www.chictr.org.cn/ under registration number ChiCTR2400080268 on January 25th, 2024.

The Lepidoptera, butterflies and moths, display an astonishing diversity of spatial orientation strategies essential for survival, reproduction, and ecological success. These spatial orientation strategies range from basic taxes to light, wind, gravity, and chemical cues, to more advanced strategies such as straight-line dispersal, multigenerational migration across continents, and complex trap-lining foraging involving long-term spatial memory. These orientation behaviours are tightly integrated with the ecological roles of lepidopterans as pollinators, prey, and bioindicators, and are supported by a flexible neuronal network. Of special interest for successful orientation are higher-order integration centres like the mushroom bodies (centres for learning and memory) and the central complex (the centre for spatial orientation and locomotion). These centres support cue integration, compass orientation, memory, and directional decision-making. However, anthropogenic stressors, including habitat fragmentation, light pollution, pesticides, and electromagnetic noise, threaten both the environmental cues and the neural systems facilitating lepidopteran navigation, with potential cascading effects on biodiversity and ecosystem health. By combining insights from behavioural ecology, neurobiology, and conservation, we aim to provide a comprehensive overview of the challenges and adaptations that shape the navigational toolkit of lepidopterans, underlining their significance as animal models for studying spatial orientation in a changing world.

Sex differences are crucial to understanding neuropsychiatric disorders, yet they are often overlooked in the development of therapies. Transcranial alternating current stimulation (tACS) shows promise for cognitive enhancement, but its sex-specific effects are largely unknown. In this study, the effects of 10Hz and 40Hz tACS on spatial cognition were examined in male and female mice using three tests: the Y-maze to evaluate spatial recognition memory, the Barnes maze to evaluate spatial learning and memory related to punishment, and the reversal Barnes maze to evaluate reversal learning. General behaviors, such as anxiety, exploration, and locomotion, were evaluated using the elevated plus maze and open field tests. The results showed that 40Hz tACS improved spatial recognition memory in males, while 10Hz and 40Hz tACS enhanced spatial learning in females. Males learned faster, while females performed better initially in the spatial learning process. In addition, no significant effects of tACS were observed in reversal learning, spatial memory, anxiety, or exploration. Interestingly, males exhibited reduced locomotion compared to females across tasks, and tACS potentially exacerbated this difference. This animal study suggests that tACS may influence spatial cognition differently in males and females. Our findings highlight the importance of considering the interaction between sex and stimulation frequency when optimizing tACS intervention parameters.

Background: The Wnt/β-catenin signaling pathway plays a pivotal role in embryonic development, maintenance of the central nervous system, and the formation of neuronal circuits. Disruption of this pathway is closely associated with oncogenesis and neurodegenerative diseases, notably Alzheimer’s disease. Flavonoids such as quercetin derivatives have emerged as promising neuroprotective agents. This study investigates the impact of 3-O-methylquercetin (3OMQ), a methylated quercetin metabolite, on Wnt/β-catenin signaling and its potential relevance in neurodegenerative disease models. Methods: The ability of 3OMQ to modulate Wnt/β-catenin activity was analyzed using a luciferase-based reporter assay in both neural and non-neural cell lines. Cell viability assays evaluated cytotoxicity at various concentrations. We mapped 3OMQ activity within the pathway using targeted cell signaling experiments. Docking and molecular dynamics simulations suggested glycogen synthase kinase 3β (GSK3β) as a putative target of 3OMQ. Finally, we employed a mouse model of acute amyloid-β oligomer (AβO) toxicity to assess the in vivo effects of 3OMQ on spatial memory and Wnt-related gene expression. Results: We compared the flavonoids quercitrin, quercetin, and 3-O-methylquercitrin (3OMQ) with pharmacologically active compounds in a gene reporter assay (TOPFLASH) using Wnt-sensitive RKO cells treated with Wnt3a-conditioned medium. XAV-939 and PNU-74654 showed inhibitory activity, while BIO, CHIR99021, quercitrin, and 3OMQ enhanced the Wnt/β-catenin pathway. Notably, 3OMQ potentiated this pathway at concentrations 5–10 times lower than quercitrin and outperformed 1 μM BIO at 10 μM without cytotoxicity, highlighting its remarkable potency. Mechanistically, 3OMQ acts downstream of initial membrane activation and upstream of the β-catenin destruction complex. Consistently, molecular docking indicates a strong interaction with GSK3, a central regulator of the pathway. In adult mice, 3OMQ administration prevented AβO-induced recognition memory deficits and favored normalization of Wnt-related gene expression. Conclusions: These findings identify 3OMQ as a potent positive modulator of the Wnt/β-catenin pathway, with both in vitro and in vivo neuroprotective effects. Targeting Wnt signaling with compounds such as 3OMQ holds promise for maintaining neuronal health and developing therapeutic strategies for neurodegenerative conditions.

Dexmedetomidine (Dex), an α2 adrenergic receptor agonist, has been shown to exert protective effects against postoperative neurocognitive disorder (PND) following anesthesia and surgery. This study aimed to investigate the underlying mechanisms, with a focus on the inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-chaperone glucose-regulated protein 75 (GRP75) calcium transport protein complex-mediated mitochondrial dysfunction. An in vitro sevoflurane-induced SH-SY5Y cell injury model and an in vivo PND rat model induced by sevoflurane anesthesia plus laparotomy were established, and both models were pretreated with Dex. Subsequent assessment included cell viability, apoptosis, inflammatory cytokines, reactive oxygen species (ROS), mitochondrial calcium ion (Ca2+), mitochondrial membrane potential (MMP), mitochondrial ultrastructure, and ATP production. Cognitive functions including spatial memory, anxiety-like behavior, and recognition memory were evaluated in rats. The expression levels and interactions among IP3R, GRP75, and VDAC1 were examined to elucidate the mechanisms involved. Sevoflurane exposure reduced cell viability, increased apoptosis and inflammation, and induced mitochondrial impairments including ROS overproduction, Ca2+ overload, loss of MMP, ultrastructural damage, and reduced ATP production. Dex pretreatment effectively alleviated all these cellular injuries. Furthermore, Dex alleviated cognitive deficits in PND rats and mitigated neuronal loss, histological damage, apoptosis, neuroinflammation, and mitochondrial ultrastructural damage in hippocampal tissues. Mechanistically, Dex reversed sevoflurane-induced upregulation of IP3R, GRP75, and VDAC1 and disrupted their enhanced interaction. VDAC1 exhibited the most pronounced changes in response to both sevoflurane injury and Dex treatment. Rescue experiments suggested that VDAC1 overexpression abrogated Dex-mediated mitochondrial protection. Dex alleviates cognitive deficits in PND rats by preserving mitochondrial calcium homeostasis and mitigating mitochondrial dysfunction through regulating the IP3R-GRP75-VDAC1 complex. This study may provide critical insights into the neuroprotective mechanisms of Dex in PND and identify potential therapeutic targets.

Abstract As computational thinking (CT) becomes increasingly integrated into K–12 education worldwide, there is a growing need to understand the cognitive foundations that support its development. Spatial abilities have been recognized as an important factor related to CT. However, prior studies have often used single-task measures such as mental rotation to represent spatial skills, which oversimplifies their multidimensional nature. In addition, research on early elementary school children remains limited, making it difficult to understand how spatial abilities influence CT during this critical stage of development. This study addresses these gaps by examining the relationship between CT and four subdimensions of spatial ability (intrinsic static, intrinsic dynamic, extrinsic static, and extrinsic dynamic). A total of 237 students aged 6 to 10 completed a battery of tasks for assessing CT and different dimensions of spatial ability. Multiple linear regression analyses were conducted with CT performance as the dependent variable and the four spatial subdimensions as the independent variable, while age, gender, and coding experience were included as control variables to ensure the robustness of the results. The results showed that all four spatial subdimensions significantly predicted CT performance, even after controlling for the covariates. These findings contribute to a deeper understanding of the cognitive basis of CT by demonstrating the role of diverse spatial skills in its development. The study highlights the importance of incorporating varied types of spatial training in early education and provides empirical support for integrating spatial learning into STEM curricula.

Since the 1960s, Geography educators have used digital technologies such as GIS and remote sensing to enrich spatial learning. The rise of artificial intelligence (AI) extends these tools by enabling transformative, data-driven, and personalised learning experiences while fostering essential 21a Century skills. However, many educators remain unaware of AI’s potential benefits and risks. Situated within South Africa’s unequal digital landscape, this study aims to raise awareness and broaden Geography educators’ understanding of effective and ethical AI integration in Geography education. It proposes a hybrid TPACKPlace- AI framework that extends the established Technological, Pedagogical and Content Knowledge model through insights from a critical pedagogy of place. The framework emphasises that AI integration must be pedagogically sound and socially responsive, foregrounding ethics, justice, power, and context. The paper thus offers a theoretical foundation for critically engaging with AI in Geography education.

The activity of hippocampal place cells is essential for various processes of spatial memory, including encoding, consolidation, and retrieval. However, whether they also participate in spatial memory updating remains elusive. This study demonstrates that during the process of long-term spatial associative memory updating, triggered by changes in reward magnitudes in a maze over consecutive days, there is a distinct period characterized by loss of preference for different reward magnitudes before adapting to new magnitude ratios. During this period, sequential replays in the hippocampus during post-training sleep are significantly biased toward the region associated with the larger reward. Additionally, replays between trials show elevated predictive power for the upcoming choices. Our results suggest that hippocampal replays may play a key role in updating long-term spatial associative memory.

Intimate partner violence (IPV) poses a significant medical concern, predominantly affecting females. IPV-related brain injuries (IPV-BI), such as mild traumatic brain injury (mTBI) and non-fatal strangulation (NFS), sustained during physical attacks are common and often repetitive. Chronic neurobehavioral sequalae from IPV-BI are associated with neuroinflammation and impaired neuroplasticity, and effective treatment options are scarce, particularly in the context of IPV. However, psilocybin, a 5-HT2A receptor agonist with therapeutic potential in psychiatric disorders that share overlapping pathophysiology as BI, is a promising candidate. This study evaluated psilocybin's effects on behavior, cognition, and neurobiology in a novel rat model of recurrent IPV-BI. Female rats underwent daily mTBI (lateral impact) followed by NFS (90 s) for five days, followed by 16 weeks of recovery. Rats then received a single intraperitoneal injection of psilocybin (1 mg/kg) or saline, with behavioral testing 24 h later. To investigate whether psilocybin's effects were 5-HT2A receptor dependent, additional rats received pre-treatment with selective 5-HT2A receptor antagonist M100907 (1.5 mg/kg) one hour before psilocybin administration. Psilocybin recovered mTBI+NFS-induced abnormalities in the elevated plus-maze, increased sucrose preference when administered without M100907, and improved reversal learning in the water maze and spatial memory in the Y-maze. In the dorsal hippocampus, mTBI+NFS rats treated with saline, but not those treated with psilocybin, exhibited an increased number of microglial cells in the molecular layer and fewer reelin-positive cells in the subgranular zone. These findings suggest psilocybin's antidepressant, pro-cognitive, anti-inflammatory, and neuroplasticity-enhancing effects hold promise for improving chronic IPV-BI outcomes and highlight the critical role of 5-HT2A receptors in mediating psilocybin's therapeutic benefits.

BackgroundIron overload plays a role in the pathogenesis of neurodegenerative disorders by inducing oxidative injury in the brain. Centella asiatica (L.) Urb. It is a medicinal plant with neuroprotective effects that exhibits antioxidant and anti-inflammatory activities. A standardized extract of C. asiatica (ECa 233) has high concentrations of the bioactive compounds madecassoside and asiaticoside. It may have potential for use in iron overload conditions.ObjectivesThis study aimed to investigate the effects of ECa 233 on iron-induced brain injury, memory deficits, and impaired locomotor activity in 12-month-old wild-type (WT) and β-thalassemia (β-globin knockout, BKO) mice with iron overload.MethodsWT and BKO mice were intraperitoneally (i.p.) injected with 100 mg of iron, followed by i.p. injection of 20 mg/kg body weight of ECa 233 for 10 days. Iron accumulation and injury in the brain were evaluated via hematoxylin and eosin (H&E) and Prussian blue staining. The Morris water maze (MWM) and open field tests were performed to evaluate spatial learning and memory and locomotor activity, respectively.ResultsAging BKO mice resulted in spontaneous iron accumulation in the brain and poor performance in the MWM test. Iron overload significantly increased brain iron content and worsened brain injury, locomotor activity, and performance in the MWM test in both WT and BKO mice. Treatment with ECa 233 significantly decreased iron accumulation in the brain and reversed brain damage in WT and BKO mice to the same extent. In addition, ECa 233 improved iron-induced memory deficits in WT mice and locomotor activity in iron-overloaded WT and BKO mice.ConclusionThese results suggest that the beneficial effect of ECa 233 may be partially due to decreased iron accumulation in the brain. ECa 233 may be used as an adjuvant with an iron chelator to prevent iron-induced neurodegenerative complications in individuals with β-thalassemia.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-025-05145-w.

Irisin, a myokine cleaved from its precursor FNDC5 (Fibronectin type III domain-containing protein 5) following exercise or low-frequency whole-body vibration, regulates energy metabolism and insulin sensitivity. This study examines irisin's therapeutic potential in stroke in rats. Adult Sprague-Dawley rats of both sexes underwent transient middle cerebral artery occlusion (90 minutes) or sham surgery. After 4.5 hours, they were randomized to receive saline or irisin treatment (0.1, 0.2, and 0.8 μg/g body weight). Infarct volume was quantified 1 day after transient middle cerebral artery occlusion using 2,3,5-triphenyltetrazolium chloride staining. In a subsequent study, reproductively senescent female rats received either saline or 0.2 μg/g body weight irisin at 4.5 hours posttransient middle cerebral artery occlusion, followed by weekly treatments for a month. Sensorimotor and cognitive functions were assessed using the cylinder test and Morris water maze. Ipsilateral cortical tissue was collected from a subset of the reproductive senescence rats following 2 weeks of treatment for RNA sequencing and real-time qPCR analysis. Irisin (0.2 μg/g) significantly reduced infarct volume by 50% in females and 36% in males compared with their respective saline groups. In reproductive senescence females, irisin treatment for a month improved contralateral limb use by day 7 and enhanced spatial learning in the Morris water maze, reducing latency to find the hidden platform on the fourth day of testing (16.5 sec versus saline; P<0.05) and increasing time spent in the target quadrant during the probe trial (9.3 sec versus saline; P<0.05). Irisin therapy significantly altered cortical gene expression, with 332 genes upregulated and 136 downregulated. Gene ontology analysis revealed genes linked to the extracellular matrix were significantly upregulated, which was confirmed by increased expression of the cell-surface integrin αVβ5, known to interact with irisin. Posttransient middle cerebral artery occlusion irisin therapy modulates the transcriptome, enhancing motor and cognitive function while protecting against ischemic brain damage in middle-aged female rats.

The retrosplenial cortex (RSC) is a critical brain region that is activated during spatial memory tasks and plays a crucial role in the consolidation of long-term memory. Various classes of RSC excitatory neurons across different laminar layers serve as the central hub for neuronal connections between the RSC and other brain regions, such as the hippocampus. Despite the established role of the RSC in spatial memory, the transcriptomic signature of the neuronal subtypes in the RSC during spatial memory consolidation remained elusive. Here, we used unbiased and targeted spatial transcriptomics to identify the RSC transcriptional signature after a spatial memory task. Genes related to transcription regulation, protein folding, and mitogen-activated protein kinase pathways were upregulated in the RSC during an early time window of memory consolidation. Furthermore, cell-type and excitatory neuronal layer-specific changes in gene expression were resolved using Xenium spatial transcriptomics. A deep learning computational tool uncovered cell-type-specific molecular activation patterns within the RSC after learning. Conversely, in a mouse model of Alzheimer's disease and related dementia (ADRD) exhibiting tau hyperphosphorylation in the RSC, there was a reduction in predicted neuronal activation following learning. Notably, learning-induced Fos expression was decreased in excitatory neurons of the RSC in the ADRD mice. Finally, we observed that blocking RSC excitatory neurons during the early temporal window after learning using a chemogenetic approach impaired long-term spatial memory in adult mice. Our results reveal a molecular signature of the RSC after learning and emphasize the role of RSC excitatory neurons during spatial memory consolidation.

Introduction: Alzheimer’s Disease (AD) is associated with cerebral microvascular dysfunction and metabolic alterations. We hypothesized that activation/overproduction of PKC contributes to AD related cerebral microvascular endothelial dysfunction. The objective of this study was to investigate whether inhibition of PKC protects against cerebral microvascular endothelial dysfunction in the setting of Streptozotocin (STZ)-Induced AD mice. Methods: Mice (C57BL/6J, 10–12-month-old, male) received a single dose of STZ (3mg/kg, 3μl) intracerebroventricular (ICV) injection or citric buffer (control group). After one week of STZ-ICV injection (AD), some of the mice received the selective PKC inhibitor LY333531 (LY) treatment (10mg/kg, oral gavage). The control (n=6), STZ-AD (n =6) and the STZ-AD + LY (n =6) mice then underwent the Morris Water Maze test for assessing spatial learning and memory and in-vitro cerebral microvascular (pial arterioles) myography for examining microvascular reactivity. Mouse brain tissue samples were also harvested for protein analysis and mouse brain microvascular endothelial cells (MBMECs)were isolated/cultured for ion channel recording via whole cell patch clamp methods. Results: Increased phospho-PKCβ and phospho-Tau (S202/T205), partially impaired spatially learning/memory and reduced cerebral microvascular relaxation were observed in mice with STZ-AD. Chronic treatment with LY partially reversed STZ-AD-impaired spatial learning and memory by showing a significant decrease in escape latency of STZ-AD mice over time compared with STZ-AD alone (P&lt;0.05). Furthermore, treatment with LY significantly improved cerebral microvascular relaxation in response to the endothelium-dependent vasodilator NS309 as compared to STZ-AD alone (P&lt;0.05). There were no significant differences in response to the endothelium-independent vasodilator SNP among the three groups, control, STZ-AD and STZ-AD +LY. Treatment with LY significantly improved MBMECs’ endothelial SK channel currents. Conclusions: Our research presents novel findings which investigate the role of PKC inhibition in restoring cerebral microvascular function and in improving endothelial SK channel function in AD in the STZ-AD mice.

Non-contact vital sign monitoring in Pediatric Intensive Care Units is challenged by frequent occlusions, data scarcity, and the need for temporally stable anatomical tracking to extract reliable physiological signals. Traditional detectors produce unstable tracking, while video transformers are too computationally intensive for deployment on resource-limited clinical hardware. We introduce Divided Space–Time Mamba, an architecture that decouples spatial and temporal feature learning using State Space Models to achieve linear-time complexity, over 92% lower than standard transformers. To handle data scarcity, we employ self-supervised pre-training with masked autoencoders on over 50 k domain-specific video clips and further enhance robustness with multimodal RGB-D input. Our model demonstrates superior performance, achieving 0.96 mAP@0.5, 0.62 mAP50-95, and 0.95 rotated IoU. Operating at 23 FPS (43 ms latency), our method is approximately 1.9× faster than VideoMAE and 5.7× faster than frame-wise YOLOv8, demonstrating its suitability for real-time clinical monitoring.

The perinatal environment has been suggested to participate in the development of tauopathies and Alzheimer's disease but the molecular and cellular mechanisms involved remain contradictory and under-investigated. Here, we evaluated the effects of a maternal high-fat diet (HFD) during lactation on the development of tauopathy in the THY-Tau22 mouse strain, a model of progressive tau pathology associated with cognitive decline. During lactation, dams were fed either a chow diet (13.6% of fat) or a HFD (58% of fat). At weaning, offspring were fed a chow diet until sacrifice at 4 months of age (the onset of tau pathology) or 7 months of age (the onset of cognitive impairment). During lactation, maternal HFD increased body weight gain in offspring. At 3 months of age, maternal HFD led to a mild glucose intolerance only in male offspring. Moreover, it impaired spatial memory in both male and female 6-month-old offspring, with males being more impacted. These cognitive deficits were associated with increased phosphorylation of hippocampal tau protein-observed at 4 months in males and at 7 months in females, highlighting a sex-specific temporal shift. Additionally, maternal HFD modified adult hippocampal neurogenesis (AHN), leading to an increase of mature neuronal cells number in females and of dendritic arborization length in males. Synaptic analysis further revealed that maternal HFD led to synaptic loss only in males. Finally, multi-omics approaches showed that maternal HFD has long-term consequences on both transcriptome, proteome and regulome, this effect being also sex-dependent with mitochondrial pathways, ribosomal activity, cilium and the extracellular matrix predominantly impacted in males, while gliogenesis, myelination and synaptic plasticity were primarily affected in females. Regulome analysis suggested that this sex-dependent phenotype was more related to a temporal shift rather than distinct sex-specific alterations. Collectively, our data suggest that maternal HFD accelerates the development of tauopathy in THY-Tau22 offspring, with sex-dependent effects, males being impacted earlier than females. These findings highlight that exposure to maternal HFD represents a critical window of vulnerability, and potentially of opportunity, for interventions aimed at preventing the development of neurodegenerative diseases.

KMT2C (histone lysine N-methyltransferase 2C, also known as MML3, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), with 79% of patients harboring KMT2C variants having ASD. However, the causal link between KMT2C haploinsufficiency and ASD remains unclear. KMT2C/MLL3 encodes a histone methyltransferase, a core protein of the KMT2C/D COMPASS (complex proteins associated with Set1) complex, which plays fundamental roles in chromatin modification, occupancy, and gene expression. The expression of KMT2C/Kmt2c peaks during the developmental period in the human/mouse brain, which indicates the critical roles of KMT2C/Kmt2c in neurodevelopment. Here, we investigated the impact of germline Kmt2c haploinsufficiency on autism-like behavioral deficits in mice, which modeled humans carrying diverse KMT2C variants. Compared with Kmt2c+/+ controls, Kmt2c haploinsufficiency mice had normal motor function without anxiety-like behaviors. Notably, Kmt2c haploinsufficiency mice exhibited autism-like social deficits and increased self-grooming in both males and females, which recapitulated the core phenotypes of ASD patients. Novel object recognition and spatial memory deficits were observed in male and female Kmt2c haploinsufficiency mice. This study reveals a causal link between Kmt2c haploinsufficiency and ASD-like behavioral deficits. These germline Kmt2c haploinsufficiency mice can be used for further studying the molecular mechanisms and developing therapeutic interventions for KMT2C haploinsufficiency-associated behavioral deficits.

Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by continuous cognitive deterioration, primarily resulting from the accumulation of amyloid-β (Aβ) plaques and tau-induced neurofibrillary tangles (NFTs). Recent studies have also highlighted histone deacetylase 3 (HDAC3) as a critical suppressor of synaptic plasticity. Although pharmacological inhibition of HDAC3 has been shown to facilitate long-term potentiation (LTP), the precise relationship between HDAC3 activity and AMPA receptor signaling, key components in LTP induction and maintenance, remains insufficiently understood. Electroacupuncture (EA), known to modulate epigenetic markers like H3K9/H3K27 acetylation and HDAC3/4 activity, may offer therapeutic potential by targeting these pathways. Here, we investigated EA's effects on AD-related pathology in APP/PS1 transgenic mice, focusing on HDAC3-AMPA receptor interactions in synaptic plasticity. Behavioral assays (Morris water maze) and electrophysiological recordings revealed that EA improved spatial learning ability and reinstated LTP in APP/PS1 transgenic mice. Mechanistically, EA reduced hippocampal HDAC3 expression while upregulating GluR1/GluR2 subunits and increasing acetylated H3K9K14/H3 levels, suggesting HDAC3-mediated transcriptional regulation of AMPA receptor genes. Co-immunoprecipitation assays further supported HDAC3's physical interaction with AMPA receptor components. Crucially, conditional knockout of HDAC3 in neurons rescued both LTP impairments and memory deficits, reinforcing its pivotal role in synaptic dysfunction. Our findings unveil a novel epigenetic mechanism whereby EA mitigates AD-associated synaptic damage by suppressing HDAC3 and enhancing AMPA receptor-dependent plasticity, highlighting HDAC3 as a promising therapeutic target for AD intervention.

We assessed the effect of the 5-HT1A receptor (R) antagonist WAY100,635 on motor behaviors, object place learning and the regional levels of dopamine (DA), serotonin (5-HT) and their metabolites in the rat brain. After a single dose of either WAY100,635 (0.4 mg/kg) or vehicle (0.9% NaCl), recognition memory was assessed together with motor/exploratory behaviors. After sacrifice, regional DA, 5-HT and metabolite levels were determined with HPLC. Overall activity and exploratory behavior were reduced by WAY100,635. Object place recognition did not differ between treatments. WAY100,635 promoted DA metabolization (1) by both monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT) in cingulate, caudateputamen, thalamus and cerebellum, (2) solely by MAO in dorsal hippocampus and (3) solely by COMT in ventral hippocampus and brainstem, but suppressed DA metabolization (by both MAO and COMT) in nucleus accumbens. It promoted 5-HT metabolization (by MAO) in cingulate, caudateputamen, dorsal hippocampus and brainstem, but suppressed it in nucleus accumbens, thalamus and cerebellum. WAY100,635 altered activity and exploratory behavior as well as the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways.