Editor's note and erratum for the Research Article "Neurexin-2: An inhibitory neurexin that restricts excitatory synapse formation in the hippocampus" by P.-Y. Lin etal.

Phosphatase and tensin homolog on chromosome 10 (PTEN) is a key negative regulator of the AKT/mTOR signaling pathway. Mutations in PTEN are highly implicated in Autism Spectrum Disorder (ASD), epilepsy, congenital hydrocephaly, and macrocephaly. While the conditional genetic knockout of Pten in murine neurons results in hypertrophy, increased migration, excitatory synaptogenesis, hyperexcitability, and epileptiform activity, the specific downstream signalling mediators of these pathologies remain to be fully elucidated. Using retroviral-mediated genetic manipulation of individual neurons within the Cre-lox system, we have analyzed pathway outputs in response to the manipulation of various genes using immunohistochemistry, confocal microscopy, and extensive morphological analyses, alongside whole-cell patch-clamp electrophysiology and 120-hour video-EEG monitoring for seizure assessment. Here, we demonstrate that signaling through AKT is necessary for the development of neuronal overgrowth, increased excitatory synapse formation, excessive migration, and hyperexcitability fueled by the loss of PTEN function. Notably, the concurrent deletion of Akt1 and Akt3 isoforms was sufficient to effectively rescue hypertrophic neuronal morphology and physiology. These findings establish AKT as the essential mediator through which PTEN deficiency manifests, providing a transformative therapeutic target to correct the morphological and functional defects central to PTEN-related neurodevelopmental disorders.

Long-term regulation of inhibitory synaptic strength is crucial for maintaining excitation-inhibition (E/I) balance in cortical circuits. In this study, we identify neuroligin-2 (Nlgn2) as a critical mediator of inhibitory long-term potentiation (iLTP) in hippocampal CA1 pyramidal cells (PCs). Using neurolide-2, a synthetic dendrimeric peptide that selectively interferes with Nlgn2-neurexin binding, in combination with whole-cell recordings in mice hippocampal slices, we show that this interaction is required to maintain NMDA-induced iLTP. Disruption of Nlgn2-neurexin interactions blocked gephyrin clustering during iLTP and prevented Nlgn2 recruitment to GABAergic synapses, without effecting baseline inhibitory transmission. Immunostaining revealed that NMDA-induced enlargement of synaptic Nlgn2 clusters occurred selectively in the CA1 stratum oriens and was abolished by neurolide-2. Temporally controlled peptide application revealed a brief, 10-minute post-induction window during which Nlgn2-neurexin adhesion is required for iLTP consolidation, and later application had no effect. Optogenetic experiments further demonstrated that NMDA-induced iLTP at both somatostatin (SST) and parvalbumin (PV) inputs depends on Nlgn2. In a more physiological paradigm, high-frequency stimulation of excitatory inputs paired with postsynaptic CA1 PC depolarization triggered heterosynaptic iLTP selectively at SST→PC synapses, which was unaffected during induction but failed to consolidate when Nlgn2-neurexin interaction was blocked, whereas excitatory LTP and PV-mediated inhibition remained intact. These findings identify perisynaptic Nlgn2-neurexin adhesion as an activity-dependent mechanism supporting inhibitory plasticity depending on input identity and induction protocol. Disruption of this process may impair inhibitory circuit remodeling, contributing to E/I imbalance in neurodevelopmental and psychiatric disorders.Significance Statement The brain remains flexible and learns by adjusting the strength of excitatory and inhibitory synapses. While excitatory plasticity is well characterized, the rules guiding the induction and consolidation of inhibitory plasticity are less clear. We found that neuroligin-2, an adhesion protein that organizes inhibitory synapse formation, is also essential for inhibitory plasticity in the hippocampus, a brain region important for memory. Moreover, interference with neuroligin-2-dependent adhesion can erase already developed inhibitory plasticity within a short time window after induction, without affecting simultaneous plastic changes at excitatory synapses. These results highlight the consolidation phase of inhibitory plasticity and identify a mechanism that, if disturbed, may contribute to epilepsy, autism, and schizophrenia, which are linked to neuroligin-2 dysfunction.

Cell fate transitions require coordinated remodeling of intracellular organelles, but how organelle morphology and interactions rewire during neurogenesis remains unclear. Here we combine multispectral imaging with quantitative organelle signature analysis to simultaneously map eight organelles as human induced pluripotent stem cells differentiate into forebrain-like neurons. We find compartment and time-specific rescaling of organelles and a progressive increase in higher-order membrane contacts, with mitochondria emerging as an early interaction hub. Later, endoplasmic reticulum (ER)-organelle contacts dominate with ER-peroxisome contacts promoting ether lipid biosynthesis, membrane homeostasis and synapse formation. Disrupting this contact impairs plasmalogen production, synaptic organization, and neuronal activity, identifying the ER-peroxisome axis as a key regulator of neuronal maturation.

Oligodendrocytes are highly specialized neural cells that produce myelin, essential for rapid electrical conduction of neural signals in the central nervous system (CNS). The emergence of oligodendrocytes and myelin was a critical step in the evolution of vertebrates and fundamental for the development of the mammalian connectome, and indispensable for miniaturization and enhanced computing power of the brain. The advance in cognitive capacity is paralleled by increasing eminence of white matter, composed of interconnected bundles of myelinated axons; white matter volume increases from 6% of the brain in shrews, considered related to the most primitive mammals, up to 50% in Homo sapiens. Myelinating oligodendrocytes together with smaller populations of oligodendrocyte precursor cells (OPCs) and satellite or perineuronal oligodendrocytes account for more than half the glial cells in the human brain. Together, these three cell types make up the oligodendroglial cell lineage that express common lineage specific proteins and transcription factors and display a degree of molecular and functional diversity. OPCs are the most numerous oligodendroglial cells during developmental axonal myelination, which extends postnatally for many years in humans. The generation of myelinating oligodendrocytes from OPCs throughout life continues to be important for adaptive plasticity of neural circuits and myelination of new axons required for learning. Myelination decreases in the aging brain and correlates with natural or physiological age-related cognitive decline. Like all neural cells, oligodendroglia express a wide assortment of ion channels, transporters, and neurotransmitter receptors that are essential for maintaining neuronal signaling, principally myelination, axonal metabolic support and homeostatic regulation of the periaxonal microenvironment. Notably, OPCs are unique amongst neuroglia in that, like neurons, they are electrically excitable and form synapses with neurons. Oligodendroglial cells also contribute to neuroplasticity through multiple mechanisms including axon guidance, synapse formation and adaptive myelination. In short, oligodendroglia are essential for normal CNS integrity, cognitive function and behavior.

Perinatal brain injury (PBI) is a leading cause of long-term neurological deficits in newborns, yet effective therapies are limited. At the cellular level, PBI involves hypoxic-ischemic stress, neuroinflammation, oxidative damage, excitotoxicity, and disrupted neurovascular and glial development. Traditional animal models and 2D cultures cannot fully capture the spatiotemporal complexity of the developing human brain, highlighting the need for more physiologically relevant systems. Human brain organoids have emerged as advanced three-dimensional models that recapitulate region-specific cytoarchitecture, neuronal and glial differentiation, and early circuit formation. They enable modeling of hypoxic-ischemic and inflammatory insults, allowing for the study of injury-induced changes in neurogenesis, gliogenesis, synaptic development, and cell interactions. Organoids facilitate identification of molecular pathways involved in injury and repair, supporting therapeutic target discovery. Using patient-derived induced pluripotent stem cells, organoids also allow personalized pharmacogenomic studies to assess genotype-dependent drug responses and toxicity. Despite limitations such as variability, lack of vascularization and immune components, and ethical considerations, brain organoids offer a promising platform to bridge developmental neurobiology and translational therapeutics, paving the way for targeted and individualized interventions in PBI.

Autologous tumor-infiltrating lymphocyte (TIL) therapy holds transformative potential for solid tumors, yet its efficacy in glioblastoma remains limited by T cell exhaustion and immunosuppression. In the current study, we optimized an effective and reliable method for in vitro expansion of TILs from glioblastoma lesions and assessed their tumor-killing capacity both in vitro and in vivo. Single-cell RNA sequencing (scRNA-seq) of expanded TILs uncovered their heterogeneity and identified a cytotoxic tissue-resident memory (TRM) CD8+ TIL subset with a unique exhaustion signature. Notably, the co-stimulatory factor GITR (encoded by TNFRSF18) is highly expressed not only on immunosuppressive regulatory T (Treg) cells but also on exhausted CD8+ TILs. GITR agonism via αGITR antibody achieved dual effects: it directly enhanced CD8+ TIL activation while simultaneously abrogating Treg-mediated immunosuppression. This dual-action mechanism synergized with αPD-1 therapy to amplify TIL reactivation, significantly enhancing tumor control in vivo. Mechanistically, GITR activation potentiated anti-tumor responses by promoting immunological synapse (IS) formation and function in TILs via the NF-κB/KALRN signaling axis. Our findings established GITR as a crucial regulator of CD8+ TIL anti-tumor immunity, positioning GITR targeting as a novel strategy to improve TIL therapy for glioblastoma, with promising implications for clinical application.

ABSTRACTSynaptic formation impairment is closely correlated with cognitive impairment in Alzheimer's disease (AD), yet the underlying mechanisms remain incompletely understood. Emerging evidence indicates that extracellular vesicles (EVs), critical mediators of intercellular communication, are implicated in the progression of AD. However, the specific mechanisms through which neuron‐derived EVs contribute to synaptic formation impairment in AD remain unexplored. In this study, we characterized EVs derived from primary neurons of APP/PS1 transgenic mice (APPNEVs) and investigated their impact on synapse formation. Transmission electron microscopy, nanoparticle flow cytometry, and immunoblotting confirmed that APPNEVs and WT neuron‐derived EVs (WTNEVs) had similar morphology, size, and canonical small EVs markers. We further revealed that APPNEVs significantly impaired neuronal synapse formation by downregulating synaptic proteins PSD95 and Synaptophysin (SYP), reducing total synapse number, and shifting synapse morphology toward immature states. Proteomic profiling via mass spectrometry identified APOE as a key upregulated protein in APPNEVs. Pharmacological inhibition of APOE with EZ‐482 effectively prevented APPNEV‐induced synaptic formation impairment, APPNEV‐mediated downregulation of synaptic proteins, and the APPNEV‐induced decrease in synaptic maturity. Mechanistically, APPNEVs suppressed Rac1‐N‐WASP‐Arp2/3‐mediated filament actin polymerization, a critical pathway for synaptic spine formation, which was prevented by APOE inhibition. In vivo stereotactic injection of APPNEVs into the hippocampus of WT mice further validated their detrimental effects on synaptic integrity, which were prevented by EZ‐482 treatment. Collectively, these findings demonstrate that APPNEVs mediate synaptic damage via carrying APOE, providing novel insights into EV‐mediated neurodegeneration in AD and highlighting APOE as a potential therapeutic target for preserving synaptic formation.

Membrane-proximal binding of PSMA facilitates synapse formation with CAR and enhances antitumor activity of PSMA CAR-T cells against prostate cancer.

Chondroitin sulfate proteoglycans (CSPGs) are major components of the matrix in many tissues including the central nervous system (CNS). Interactions between extracellular CSPGs and different cell types are crucial for the development of the CNS as CSPGs are heavily involved in maintaining the pool of progenitors, neurogenesis, neuronal migration and maturation, cortical lamination, synapse formation and stabilization, neuronal plasticity, and memory formation. CSPGs play distinct roles in CNS development and pathology. While physiologic levels of CSPGs have key roles in CNS development, CNS pathologies result in upregulation of CSPGs that pose a barrier to neuroregeneration. Extensive evidence shows that pathologic CSPGs interfere with various regenerative mechanisms including axonal elongation, immunomodulation, synaptogenesis, cellular replacement, and remyelination. At the cellular level, CSPGs' effects are mainly mediated through activation of leukocyte common antigen-related receptor (LAR) and protein tyrosine phosphatase sigma (PTP-σ) receptors. Various approaches have been developed to overcome the inhibitory effects of pathologic CSPGs including enzymatic degradation of CSPGs, blocking CSPG/LAR/PTP-σ axis, and inhibition of CSPGs synthesis. Here, we will discuss the current understanding on the role and mechanisms of CSPGs in CNS development and pathologies and signaling pathways that mediate CSPGs' effects in the CNS. We will also review how CSPGs have been modulated in neurological disorders.

APOE4 induces sex-dependent synaptic mitochondrial cholesterol, proteome, and respiratory function alterations in mice.

Genetics of Autism Spectrum Disorder underscores the role of altered spontaneous neuronal activity as a catalyst for the neurodevelopmental anomalies.

Mechanism of action of REDD1 in depression and its targeted intervention.

The expanding roles of adhesion GPCRs in neural circuit assembly.

Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution-it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood-brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co-culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient-derived modelling and large-scale drug testing in BBB-relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long-term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next-generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate invitro models of the human brain-offering new opportunities for neuroscience research, drug development, and regenerative medicine.

Ephrins and Eph family proteins are key intercellular signaling molecules in the nervous system. They regulate processes such as neural development, synaptic plasticity, neural stem cell differentiation, as well as neurodegenerative diseases and neural injury repair through a unique bidirectional signaling mechanism. In recent years, with the deepening of research, the central role of Ephrin and Eph family proteins in the field of neuroscience has gradually emerged, making them a hot topic of study. The purpose of this review is to systematically explore the mechanisms of action of Ephrin and Eph family proteins and their pathways in the nervous system, revealing their critical roles in neural development, functional maintenance, and disease occurrence, while providing theoretical foundations and potential targets for the treatment of neurological disorders. The Ephrin-Eph signaling pathway plays an important role in processes such as neuronal migration, axon guidance, synapse formation and plasticity, and neural stem cell differentiation through a bidirectional signaling mechanism. Abnormalities in this pathway are closely related to the development of neurodegenerative diseases (such as Alzheimer's disease), impairments in neural injury repair, and the progression of neurological tumors. Increasing evidence highlights the core regulatory position and functional complexity of Ephrin and Eph family proteins in the processes of neural injury and repair. The review also discusses the key regulatory roles of Ephrin and Eph family proteins in neuronal migration and positioning, axon guidance, synapse formation and plasticity, as well as their important functions in neural stem cell differentiation, cell adhesion and repulsion balance, and myelin regeneration. Additionally, this review analyzes the emerging roles of Ephrin and Eph family proteins in regulating the inflammatory microenvironment after neural injury, maintaining blood-brain barrier integrity, and facilitating neural function recovery. This review also summarizes the cellular and molecular mechanisms that support these functions, particularly the dynamic regulatory network of Ephrin-Eph bidirectional signaling and its interactions with other signaling pathways, such as Wnt and MAPK. Future research needs to further elucidate the molecular mechanisms of the Ephrin-Eph signaling pathway, develop highly specific small molecule inhibitors, gene therapy, and immunotherapy strategies, and integrate interdisciplinary technologies (such as single-cell multi-omics, optogenetics, and nanotechnology) to promote clinical translation, paving new avenues for precise treatment of neurological diseases.

Glioblastoma (GBM) cells form neuron-to-glioma malignant synapses on neurite-like tumor microtubes (TMs), driving infiltrative growth and recurrence. The mechanisms underlying coordinated crosstalk among GBM cells and with neurons to favor malignant over normal synapses remain largely unknown. Here, we demonstrate that glioma-secreted C1QL1 is a key messenger for glioma-neuron and glioma-glioma crosstalk to drive TM expansion and malignant synapse formation. C1QL1 binds to its receptor BAI3 on neighboring neurons and GBM cells, activating Rac1-mediated cytoskeleton rearrangement to prune normal synapses and outgrow TMs, promoting malignant synapse and glioma network formation. Targeted treatment with a non-GEF-targeting, first-in-class Rac1 inhibitor rescues C1QL1-mediated synaptic pruning, inhibiting TMs and malignant synapses to impede glioma recurrence. Our findings elucidate how crosstalk among GBM cells and neurons allows infiltrating GBM cells to sculpt and integrate into the existing neural network, highlighting a therapeutic strategy against GBM recurrence through simultaneous inhibition of TMs and glioma-induced synaptic pruning.

Neuronal maturation involves a tightly regulated cessation of growth and acquisition of polarity, ultimately leading to synapse formation. While essential for circuit stability, maturation marks the loss of regenerative capacity after central nervous system (CNS) injury. The molecular programs coupling maturation to regenerative decline remain incompletely understood. Here, we show that the transcriptional and epigenetic signatures enabling axon growth in dorsal root ganglion (DRG) neurons are lost as they transition from immature, non-polarized cells to mature, pseudo-unipolar neurons. We identify the transcriptional co-regulator CITED2 as a key epigenetic switch, active in immature and regenerating DRG neurons but silent after non-regenerative spinal cord injury (SCI). Cited2 overexpression reactivates growth programs, enhancing regeneration in vivo after SCI. Mechanistically, CITED2 reinstates developmental epigenetic and transcriptional profiles, decoupling maturation from regenerative failure. Pharmacogenomic screening identified CITED2 as a target of the clinically approved HDAC inhibitor Panobinostat, which promoted axonal growth, sprouting, and functional recovery post-injury. These findings position CITED2 as a key regulator of sensory neuron plasticity and a novel therapeutic target for CNS repair.

Synapse formation and elimination are two crucial processes that occur concurrently in the developing brain. Astrocytes and microglia control both processes, yet how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination is unknown. Astrocytes secrete the synaptogenic protein Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Here, we found that, in addition to this synaptogenic function, Hevin directly signals to microglia by interacting with Toll-like receptor 4 (TLR4). This signaling occurs when Hevin is proteolytically cleaved, producing a C-terminal fragment that is no longer synaptogenic. We found that Hevin, through TLR4, induces a distinct microglial state defined by increased TLR2 expression and phago-lysosomal content in vitro and in vivo. Microglial TLR4 signaling is required for the proper elimination of thalamocortical synapses during early postnatal development.

Several studies have revealed deleterious synapse formation onto cancer cells within the brain tumor microenvironment, yet these synapses are ~100-fold weaker in presynaptic release rates and postsynaptic strength relative to bona fide synapses formed between neurons. Here, we find that most of the functional synapses on tumor cells are kept dormant and can be unlocked by overcoming GABAB receptor-mediated metabotropic signaling in neurons. Scavenging Gβγ signaling in neurons increased presynaptic release probability on tumor cells and augmented cancer cell proliferation. Optical analysis of the tumor microenvironment revealed regulated secretion of neurotransmitters from tumor cells in response to GABAB receptor inhibition or electrical stimulation. These results reveal how cancer cells with a high propensity for brain metastasis leverage precise moments of aberrant excitation between neurons to engage reciprocal interactions that ultimately fuel cancer proliferation.