CHKA knockout impairs dendritic development and Wnt pathway regulation in neurodevelopment.

Callosal projections connect both cortical hemispheres via the corpus callosum, allowing bilateral integration of sensory information. Callosal axons originate mainly from layer (L)2/3 pyramidal neurons in primary sensory areas and project to homotopic contralateral regions. The projections display a stereotyped layer-specific pattern, targeting distinct dendritic domains of contralateral L2/3 neurons. In mouse somatosensory cortex, such precise innervation emerges in an activity-dependent manner during the second and third postnatal weeks but the molecular determinants are largely unknown. Using in utero electroporation of fluorescent reporters to label axonal and dendritic arbors of L2/3 neurons through postnatal development, we show that loss-of-function of Grin3a (gene encoding the nonconventional NMDA receptor GluN3A subunit) disrupts region- and layer-specific contralateral targeting by callosal axons without affecting early axonal navigation or midline crossing. Rather than concentrating at the border between primary/secondary somatosensory cortex (S1/S2), callosal axons in male and female GluN3A knockout mice form a second column laterally in S2. Within the S1/S2 border, axonal arbors fail to innervate their normal destinations in L1 and outer L2/3 and shift toward inner L2/3 regions. Analysis of dendritic architecture revealed that GluN3A deletion drives proximal bifurcation and premature branching of apical dendrites of L2/3 neurons, with inward expansion of recipient dendritic trees matching callosal axon profiles in Grin3a knockouts. Together with conditional loss of function experiments, our results suggest that the dendritic patterning of postsynaptic L2/3 neurons directs the position of callosal axons within their target fields and implicate GluN3A in the postnatal timing and specificity of this process.

Our earlier human studies identified NRSN2 (Neurensin-2), a neuronal-specific vesicular protein, as a candidate gene contributing to 20p13 microdeletion syndrome, yet the functional consequences of NRSN2 deficiency in the nervous system remain poorly understood. To explore the role of Nrsn2 in neurodevelopment and cognitive function, we utilized previously generated homozygous Nrsn2 knockout mice (Nrsn2-/-) and performed a series of behavioral, morphological, and electrophysiological analyses. Behaviorally, Nrsn2-/- mice exhibited mild locomotor impairment, as assessed by gait analysis at 4 and 8 weeks of age, as well as significant deficits in spatial learning and memory (Morris water maze) and fear memory (passive avoidance test) at 8 weeks. Morphometric analysis suggested no overt alterations in dendritic complexity or spine density in hippocampal CA1 pyramidal neurons or cerebellar Purkinje cells without developmental malformation. Electrophysiological recordings and immunoblotting analyses may reflect region-specific synaptic alterations. In the hippocampus, expression levels of the NMDA receptor subunits GluN1 and GluN2A were reduced at 4 weeks of age. Consistently, CA1 pyramidal neurons displayed decreased sEPSC frequency with unchanged amplitude under the conditions examined. In addition, an imbalance in hippocampal excitatory/inhibitory transmission was observed, as reflected by altered sEPSC frequency in the absence of changes in sIPSC frequency. In cerebellar Purkinje cells, GluA1-containing AMPA receptors were selectively downregulated, accompanied by reduced frequency and amplitude of sEPSCs and a selective decrease in sIPSC frequency, indicating both excitatory and inhibitory synaptic dysfunction in this region. Collectively, these findings indicate that Nrsn2 deficiency is accompanied by altered excitatory synaptic transmission and reduced long-term potentiation (LTP) at 8 weeks of age, despite preserved dendritic architecture as assessed by Golgi staining. These synaptic and plasticity deficits occur alongside the observed cognitive and motor impairments in Nrsn2⁻/⁻ mice. This study provides a descriptive phenotypic characterization of Nrsn2 deficiency and offers initial insights into the neurobiological role of NRSN2 and its contribution to neurodevelopment, learning, and memory.

With the flourishing trend toward miniaturization and high integration of electronic devices, materials that integrate both high thermal conductivity and efficient low-frequency electromagnetic wave absorption (EMA) performance has become crucial for addressing heat accumulation and electromagnetic compatibility issue. Traditional thermally conductive EMA materials, typically fabricated by blending EMA materials with highly thermally conductive components, suffer from drawbacks such as excessive volume, high interfacial thermal resistance, and incompatibility. Herein, a cross-scale biomimetic construction strategy was employed to successfully fabricate a dendritic cell-liked heterogeneous architecture comprising nitrogen-doped carbon nanotube (NCNT) networks confining high-entropy alloy (HEA) nanoparticles. By precisely regulating the microscopic morphology of the NCNTs networks, biomimetic cross-domain coupling channels were established, formatting a distinctive magnetic-electric-magnetic hierarchical loss mechanism and a 3D efficient conductive/thermal conduction pathway simultaneously. The optimized NCNTs/HEA-2 sample achieved a minimum reflection loss (RLmin) of -57.85 dB at 6.32 GHz, with an effective absorption bandwidth (EAB) of 2.32 GHz at a thickness of 3.10 mm. Meanwhile, the increased the in-plane thermal conductivity of the NCNTs/HEA-2 up to 2.44 W·m-1·K-1, which are superior to those of most reported dual-functional materials. Furthermore, the material demonstrated excellent corrosion resistance, providing a material foundation for the thermal-electromagnetic integrated design of next-generation electronic devices.

Intravitreal delivery of NGF-chitosan hydrogel confers retinal ganglion cell protection and visual function recovery in experimental glaucoma

MicroRNAs as potential biomarkers in schizophrenia: Current methodological limitations and challenges.

Skraban-Deardorff syndrome, a rare neurodevelopmental disorder caused by WD repeat domain 26 (WDR26) haploinsufficiency, is characterized by intellectual disability, seizures, autistic-like behaviors, and craniofacial anomalies. Despite its genetic association with variants disrupting the C-terminal to LisH (CTLH) E3 ubiquitin ligase complex, the molecular mechanisms linking WDR26 dysfunction to neurodevelopmental deficits remain unclear. Here, we demonstrate that Wdr26 heterozygous-KO mice (Wdr26+/–) recapitulated core clinical features of the syndrome, including learning and memory impairments, social dysfunction, heightened seizure susceptibility, and motor deficits, alongside rare craniofacial and dental abnormalities. Mechanistically, Wdr26 haploinsufficiency stabilized RUNX1 translocation partner 1 (RUNX1T1), a transcriptional coactivator critical for neuronal differentiation, by impairing its ubiquitination and proteasomal degradation, consequently disrupting the level of microtubule-associated protein 2 (MAP2), a key regulator of dendritic architecture and synaptic plasticity. Early intervention in neonatal Wdr26+/– mice (P0.5) using AAV-shRNA–mediated Runx1t1 knockdown reversed MAP2 overexpression and behavioral deficits. Notably, the antipsychotic risperidone ameliorated cognitive and social impairments in Wdr26+/– mice by upregulating WDR26 levels, suggesting a potential therapeutic avenue. Our findings not only establish the animal model as a robust preclinical tool but also define the WDR26/RUNX1T1/MAP2 regulatory axis as pivotal to the syndrome’s pathogenesis, while identifying actionable therapeutic targets.

Normal sensitivity of the Drosophila larval nociceptor requires the activity of the Wg/WNT signaling pathway. When the nociceptor expression of Wg/WNT co-receptor Arrow, Drosophila ortholog of LRP5/6, is impaired by RNA interference, the larva becomes significantly hyposensitive to noxious thermal and mechanical stimulation. The reduced sensitivity was not associated with significant changes in dendritic architecture.

PurposePrenatal hypoxia is a major environmental risk factor for neurodevelopmental disorders, yet effective prenatal therapeutic strategies remain lacking. This study aimed to develop a transferrin-modified lipid nanoparticle platform for targeted delivery of HIF-1α siRNA to the fetal brain and to evaluate its therapeutic efficacy and molecular mechanisms.MethodsTransferrin-modified lipid nanoparticles encapsulating HIF-1α siRNA were intravenously administered to pregnant rats prior to hypoxic exposure. Biodistribution, gene silencing efficiency, molecular signaling alterations, neuronal structural changes, and behavioral outcomes in offspring were systematically assessed.ResultsIn this study, we developed a transferrin-modified lipid nanoparticle system for non-invasive, transplacental delivery of HIF-1α small interfering RNA to the fetal brain, achieving a siRNA encapsulation efficiency of 84.18% and a loading capacity of 2.5%. Systemic administration to pregnant rats prior to hypoxic exposure resulted in preferential accumulation of nanoparticles in fetal brain tissue and effective suppression of HIF-1α expression in the fetal hippocampus without overt effects on offspring survival, as evidenced by comparable offspring survival rates across all groups (p > 0.05). Prenatal hypoxia induced sustained elevation of HIF-1α protein (p < 0.001), impaired phosphatase and tensin homolog (PTEN) activity through increased phosphorylation (p < 0.01), aberrant activation of the PI3K/AKT signaling pathway (p < 0.05), and deficits in hippocampal neuronal structural plasticity, including reduced dendritic spine density (p < 0.0001) and dendritic complexity (p < 0.0001), accompanied by autism-like behaviors in offspring, including impaired social preference (p < 0.01), prolonged self-grooming (p < 0.0001), and increased marble-burying (p < 0.001). Prenatal HIF-1α silencing restored PTEN functional status, normalized PI3K/AKT signaling, improved dendritic architecture to levels comparable to controls (p > 0.05 vs control), and significantly ameliorated behavioral abnormalities (social preference and stereotyped behaviors, p < 0.0001). Mechanistic analyses revealed that although HIF-1α binds to the PTEN promoter (ChIP-qPCR, p < 0.01), prenatal hypoxia did not alter PTEN transcript or total protein levels (p > 0.05), indicating that HIF-1α primarily regulates PTEN function at the post-transcriptional level in vivo.ConclusionThese findings identify a HIF-1α/PTEN/PI3K/AKT signaling axis as a key molecular pathway underlying hypoxia-associated neurodevelopmental impairment and demonstrate the feasibility of targeted prenatal gene modulation using transferrin-modified lipid nanoparticles. This work provides a nanomedicine-based framework linking environmental risk factors to early-life preventive strategies for neurodevelopmental disorders.

Anorexia nervosa (AN) is increasingly understood as a metabo-psychiatric disorder in which metabolic biology and neural circuit function are intrinsically intertwined. Genetic studies reveal that AN is associated with heritable metabolic traits suggesting that metabolic vulnerability contributes to the disorder. The metabolic profile of AN further shapes brain responses; endocrine signals such as insulin, leptin, ghrelin, and adiponectin elicit atypical neural responses in circuits regulating appetite, reward, interoception, and cognitive control. This altered signaling is accompanied by circuit-specific remodeling, suggesting that the chronic metabolic dysregulation seen in AN affects synaptic plasticity across distributed brain regions. Neural systems that integrate metabolic, emotional, and cognitive information-including hypothalamic, striatal, prefrontal, and limbic circuits-show altered plasticity under starvation. Glucose and insulin modulate excitatory-inhibitory balance and synaptic efficacy, while ketone bodies act as starvation-associated neuromodulators influencing transmitter release and structural plasticity. These and other body-to-brain signals recalibrate network dynamics central to food intake, motivation, and learning. At the molecular level, intracellular metabolic sensors such as AMPK, mTOR, and O-GlcNAc function as transducers that convert nutrient availability into changes in protein synthesis, receptor trafficking, and dendritic spine architecture, providing mechanistic links between metabolic state and synaptic remodeling. Overall, converging evidence supports a model in which AN arises from interactions between metabolic traits and the plastic neural circuits mediating food intake, emotion, and cognition. By clarifying how metabolic signals reshape synaptic ensembles in AN, we present a framework for understanding mechanisms of vulnerability and identify targets capable of restoring adaptive plasticity. This review suggests a trajectory in which treatments jointly address metabolic physiology and brain-based processes of learning, motivation, and affect.

ABSTRACT A waste-to-wealth strategy is reported for the fabrication of a copper-functionalized fibrous nanosilica (Cu/KCC-1) photocatalyst derived from palm oil fuel ash (POFA), an abundant silica-rich agricultural residue. The Cu/KCC-1 nanocomposite retains the characteristic dendritic fibrous architecture and high surface area of KCC-1, while incorporating catalytically active Cu species within the amorphous silica framework, as confirmed by FESEM, XRD, BET, FTIR, and UV–Vis DRS analyses. The resulting catalyst exhibits outstanding photocatalytic activity toward methylene blue degradation, achieving 94.30% efficiency under UV irradiation at pH 8 with a catalyst dosage of 3 g/L and an initial dye concentration of 10 mg/L. Reaction temperature strongly influenced performance, with optimal degradation at 50°C, beyond which charge-carrier recombination and partial deactivation limited the catalytic efficiency. The superior activity is attributed to enhanced light absorption, increased density of accessible active sites, and improved charge separation induced by Cu incorporation within the fibrous silica matrix. Alkaline conditions further promoted degradation by facilitating reactive oxygen species generation. A mechanism involving surface adsorption followed by •OH− and O2•− driven oxidative mineralization is proposed. This study demonstrates the viability of POFA-derived Cu/KCC-1 as a high-performance, low-cost, and sustainable photocatalyst for advanced wastewater remediation.

Direction-selective T4 neurons are among the most abundant cells in the Drosophila visual system. Although arranged retinotopically, their dendrites do not exhibit classical tiling. Instead, the four T4 subtypes are present once within each of the 750 columns in the fly optic lobe, with their dendrites spanning seven to nine neighboring columns. This results in a dense mesh of overlapping neural processes. Such deviation from classical tiling raises the question of whether homotypic interactions among highly intermingled dendrites such as T4s still contribute to shaping of their dendritic architecture. To address this, we developed Flp2Rescue, a genetic tool that ablates most T4 neurons while stochastically rescuing solitary ones. Our findings reveal that solitary T4 dendrites exhibit significant enlargement, indicating that homotypic interactions normally constrain the dendritic size of T4 neurons. Despite this enlargement, solitary T4 dendrites preserve their main subtype-specific orientations. In the enlarged dendrites we also found a higher number of glutamatergic receptors exhibiting a broader distribution along the dendrite. Surprisingly, these changes do not alter the functional identity of the neurons, meaning solitary T4 neurons continue to respond selectively to motion in their preferred direction.

Dietary restriction mitigates cognitive impairments in a mouse model of SCA19/22.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is associated with attention deficits, hyperactivity, anxiety, impulsivity, and repetitive behaviors. The disorder results from transcriptional silencing of the FMR1 gene, leading to loss of fragile X messenger ribonucleoprotein (FMRP), an RNA-binding protein that regulates local dendritic translation by repressing ribosomal activity. To examine how impaired local protein synthesis affects dendritic organization, we used Golgi-Cox staining to analyze hippocampal CA1 principal neurons across four developmental stages (P14-21, P30-40, P60-80, and P120-150) in an FXS mouse model. We identified a progressive reduction in dendritic complexity, reflected by decreased Sholl intersections and reduced dendritic branch number and length. In contrast, spine density was increased in both apical and basal dendrites during early development but normalized to wild-type levels in adulthood. Collectively, these structural alterations are likely to disrupt neural circuit development, with downstream consequences for cognition and behavior characteristic of FXS.

Cadmium (Cd), a widespread environmental toxic metal, is linked to central nervous system dysfunction and neuronal structural damage, yet its mechanisms remain unclear. This study combined network toxicology with experimental validation to explore how Cd impairs dendritic integrity through neuroinflammatory pathways. Network analysis suggested that Cd-induced dendritic injury was likely mediated by inflammatory signaling pathways, with nuclear factor-erythroid 2-related factor 2 (Nfe2l2), a major redox regulator, highlighted as a candidate regulator. Therefore, we investigated the involvement of microglia-mediated neuroinflammation in Cd-induced dendritic damage and assessed the role of Nfe2l2 in this process, using Nfe2l2 knockout mice and Nfe2l2 knockdown BV2 microglia. Furthermore, primary neurons were co-cultured with conditioned media (CM) from Cd-treated microglia to evaluate how Nfe2l2-regulated neuroinflammation contributes to dendritic damage. Nfe2l2 deficiency aggravated Cd-induced dendritic damage in the hippocampus, manifested as significant reductions in dendritic length, intersections, and branch points. In parallel, Nfe2l2 deficiency also intensified Cd-induced microglial activation and neuroinflammation in the hippocampus. Consistently, Nfe2l2 knockdown amplified Cd-induced BV2 microglial activation, characterized by increased migratory and phagocytic activity, and the subsequent cytokine release. Subsequently, CM derived from these activated microglia further exacerbated neuronal dendritic damage. Moreover, Nfe2l2 knockdown diminished minocycline's anti-inflammatory and neuroprotective effects. These results demonstrate that Cd-induced microglial activation and inflammation are central to dendritic injury, and that Nfe2l2 is essential in protecting neurons from Cd-driven neuroinflammation.

N-methyl-D-aspartate receptors (NMDARs) in the prefrontal cortex (PFC) are critical regulators of neuronal excitability, synaptic plasticity, and cognitive function. NMDAR disruptions, including pharmacological blockade and anti-NMDAR encephalitis, can mimic symptoms of schizophrenia. These observations support the glutamate hypothesis of schizophrenia, which posits that symptoms arise from abnormal corticolimbic glutamatergic signaling. Further evidence for this theory includes abnormal expression of NMDARs and decreased dendritic spine density in the PFC of individuals with schizophrenia, as well as altered spine density and synaptic transmission caused by genetic manipulation of NMDARs. However, it is unknown how progressive loss of NMDAR function in the PFC during adolescence—a developmental time period associated with symptom onset in schizophrenia —affects excitatory synaptic structure and function. In this study, we used in vivo genome editing to ablate expression of the Grin1 gene, which encodes the obligate GluN1 subunit of NMDARs, in medial PFC neurons of female and male adolescent mice. We assessed synaptic density and function in layer V pyramidal neurons using whole-cell patch-clamp electrophysiology, integrated with confocal imaging of dendritic spine architecture in recorded neurons. NMDAR ablation caused an early decrease in basilar dendritic spine density, followed by a rebound in spine density and a corresponding increase in AMPAR-mediated synaptic transmission. These effects of pan-neuronal NMDAR ablation were not observed after a more specific manipulation of excitatory neurons. Our findings demonstrate that NMDAR ablation triggers a cascading reorganization of local PFC networks, which may include compensatory processes that maintain allostasis but are impaired in disease states.

HIV-associated neurocognitive impairment persists despite combination antiretroviral therapy, largely driven by chronic microglial activation that sustains neuroinflammation and neuronal injury. Activated microglia contribute to HIV-associated brain pathology by releasing proinflammatory mediators that disrupt synaptic integrity and impair cognition. N-acetylaspartylglutamate (NAAG), an abundant neuropeptide that maintains glutamatergic homeostasis, is hydrolyzed by glutamate carboxypeptidase II (GCPII) to glutamate. We previously demonstrated that reduced brain and cerebrospinal fluid NAAG levels in people living with HIV correlate with cognitive impairment, and that pharmacological GCPII inhibition with 2-(phosphonomethyl)-pentanedioic acid (2-PMPA) elevates brain NAAG and improves cognition in EcoHIV-infected mice. To enhance brain delivery and preferentially target activated microglia, we conjugated 2-PMPA to a generation 4 hydroxyl poly(amidoamine) (PAMAM) dendrimer (D-2-PMPA). Our findings demonstrate that D-2-PMPA achieves preferential microglial drug delivery, resulting in a >600% increase in cerebrospinal fluid NAAG levels. At doses 8.3-fold lower than free 2-PMPA, this formulation reversed EcoHIV-induced deficits in social interaction, novel object recognition, and fear-conditioned memory without altering locomotor activity or anxiety-like behavior. D-2-PMPA also restored prefrontal cortex synaptic density and preserved dendritic architecture. Together, these findings demonstrate that microglia-targeted GCPII inhibition represents a potent nanotherapeutic strategy to restore synaptic integrity and cognitive function in HIV-associated neurocognitive impairment.

Animal models are indispensable for linking human genetic findings to disease mechanisms. Mutations in protocadherin gamma C4 (γC4), one of the 22 isoforms encoded by the protocadherin-γ (Pcdh-γ) gene cluster, cause a human neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability. Here, we established a γC4 mutant mouse model that exhibits motor dysfunction, seizures, reduced brain size, and increased embryonic neuronal apoptosis. Using DOMINO (Double Mutation-Induced Open Reading Frame Switch), a two-step CRISPR/Cas9-based genome-editing strategy, we also generated γC4fl-only mice that retain full-length γC4 while truncating the other 21 Pcdh-γ isoforms. Unlike Pcdh-γ cluster-deficient mice, γC4fl-only mice were viable and fertile. Furthermore, we show that the γC4 constant region (γCR) contributes to the regulation of Purkinje cell dendritic architecture and self-avoidance. Together, these findings indicate that γCR-containing γC4 is required for neuronal survival and dendritic patterning, supporting γC4 as a principal functional isoform within the Pcdh-γ gene cluster.

Single-cell transcriptomics reveals the mechanism of long-term neurodevelopmental toxicity following sevoflurane anesthesia.

BackgroundSecond-generation antipsychotics (SGAs) are increasingly being utilized in children and adolescents. Risperidone, one of the most commonly prescribed SGAs in this population, has been found to adversely affect cognitive function; however, limited knowledge exists regarding the impact of risperidone on the gut microbiome-brain axis. We hypothesized that the cognitive impairment induced by risperidone is mediated by alterations in the gut microbiome and its metabolites.ResultsIn this study, we found that early-life risperidone exposure impaired cognition in mice, including deficits in behavior tests and hippocampal dendritic architecture. The risperidone-exposed mice also exhibited gut microbiota dysbiosis along with damage to the intestinal barrier. Fecal microbiota transplantation (FMT) from treated donors to recipients demonstrated the causal role of the gut microbiome in risperidone-induced cognitive deficits. Of note, risperidone increased the abundance of species Escherichia coli, Eggerthella lenta, Ruminococcus gnavus, Clostridium perfringens, Clostridium difficile, and Blautia hydrogenotrophica. These altered species are identified to encode 7α-HSDH, 3β/α-HSDH, TyrB, and porA, the key enzymes in secondary bile acid metabolism and tyrosine metabolism. Furthermore, a significant reduction in tauroursodeoxycholic acid (TUDCA, the metabolite of bile acid metabolism) and accumulation of p-cresol (the metabolite of tyrosine metabolism) were observed in the brains of mice exposed to risperidone. Mechanically, TUDCA prevented cognitive impairment and endoplasmic reticulum (ER) stress in the hippocampus induced by risperidone, while p-cresol induced neuronal ER stress. Knockout of protein tyrosine phosphatase 1B (PTP1B, ER stress-associated protein) in neurons ameliorated cognitive impairment and neurological damage induced by risperidone.ConclusionsThis study, for the first time, reveals that early risperidone exposure induces gut microbiome dysbiosis and disturbs the bile acids/tyrosine-PTP1B axis to impair cognitive function. These findings alert the risk of gut and neurological side effects of SGAs treatment and highlight that it is crucial to maintain gut homeostasis during the brain developmental phases of children and adolescents with SGAs exposure.Video Supplementary InformationThe online version contains supplementary material available at 10.1186/s40168-026-02358-0.