Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Editorial: Axon neurobiology: updates in functional and structural dynamics.
Kamiya H, Debanne D
Front Cell Neurosci · 2026 · PMID 42078084 · Full text
Abstract loading — click title to view on PubMed.
Comprehensive 3D mapping reveals distinct spatial gradients of genetically-identified SST, PV, and TH interneurons across the mouse caudoputamen.
Muhsinov JM, Iliakis EA, Tu W … +7 more , Ramirez AN, Muniak MA, Wasilczuk AZ, Davatolhagh MF, Proekt A, Mao T, Fuccillo MV
Front Cell Neurosci · 2026 · PMID 42078083 · Full text
INTRODUCTION: In addition to spatially organized excitatory forebrain inputs along its mediolateral, dorsoventral, and anteroposterior axes, the dorsal striatum (caudoputamen) relies on cellular diversity to subserve its...
INTRODUCTION: In addition to spatially organized excitatory forebrain inputs along its mediolateral, dorsoventral, and anteroposterior axes, the dorsal striatum (caudoputamen) relies on cellular diversity to subserve its myriad processing functions. Distinct GABAergic interneuron subtypes, including somatostatin (SST), parvalbumin (PV), and tyrosine hydroxylase (TH) interneurons likely subserve complementary computational roles. However, a detailed understanding of how these microcircuit components are distributed across the caudoputamen remains lacking. METHODS: To address this gap, we generated a comprehensive three-dimensional atlas of genetically-defined SST-, PV-, and TH- labeled interneuron populations across the mouse caudoputamen using genetic labeling, caudoputamen-wide imaging, and voxel-wise quantification. RESULTS: We found that genetically-defined SST and TH interneurons were relatively enriched in the ventral caudoputamen, whereas PV interneurons were enriched dorsally. In addition, PV and TH interneurons exhibited opposing anteroposterior distribution patterns, with PV interneurons enriched posteriorly and TH interneurons showing a marked decline in density toward the tail of the caudoputamen. Consequently, while the three interneuron subtypes displayed comparable densities in the functionally defined lateral caudoputamen and anterior ventromedial caudoputamen, PV interneurons predominated in the dorsomedial caudoputamen and tail of the caudoputamen. While some statistically significant sex differences were detected, the overall spatial distribution patterns of interneurons were similar across sexes. DISCUSSION: Together, these findings reinforce the view that the caudoputamen is not a monolithic structure: in addition to excitatory and neuromodulatory inputs, inhibitory microcircuits themselves are differentially distributed across the caudoputamen, providing region-specific constraints on circuit computation. By integrating interneuron organization into existing anatomical frameworks, this atlas provides a foundation for linking dorsal striatal anatomy to function across behavioral domains.
Cocaine remodels mA RNA-dependent signaling to drive locomotor plasticity in .
Filošević Vujnović A, Milotić N, Samardžija B … +3 more , Rubinić M, Andretić Waldowski R, Soldano A
Front Cell Neurosci · 2026 · PMID 42063981 · Full text
N-methyladenosine (mA) is a dynamic RNA modification that regulates RNA stability, processing, and translation and is increasingly recognized as a key modulator of neuronal plasticity. However, how psychostimulant exposu...
N-methyladenosine (mA) is a dynamic RNA modification that regulates RNA stability, processing, and translation and is increasingly recognized as a key modulator of neuronal plasticity. However, how psychostimulant exposure reshapes mA-dependent regulatory networks across coding and non-coding RNA species remains poorly understood. We investigated the impact of volatilized cocaine (vCOC) exposure on mA RNA methylation, mA pathway components, transcriptome, and cocaine-induced locomotor sensitization in . Acute vCOC administration significantly increased global mA levels in total and poly(A)-enriched RNA, with a stronger effect in polyadenylated transcripts. This increase occurred without changes in the mA methyltransferases Mettl3 and Mettl14 transcripts, but was accompanied by robust upregulation of the levels of mA reader YTHDC and YTHDF transcripts. Genetic and cell-type-specific analyses revealed distinct and context-dependent roles for mA writers and readers in neurons and glia, with mA readers being essential for vCOC-induced locomotor sensitization. Integration of RNA-seq and MeRIP-seq demonstrated that vCOC selectively amplifies mA modification of regulatory and plasticity-associated RNA classes, including mRNAs involved in RNA processing, antisense RNAs, long non-coding RNAs, and transposable element-derived transcripts. In contrast, mA-modified RNAs shared in CTRL and vCOC were enriched for core metabolic and mitochondrial pathways, such as oxidative phosphorylation. Notably, vCOC increased mA modification of non-coding RNAs and transposable elements with minimal overlap with control conditions, indicating cocaine-induced engagement of epitranscriptomic regulation at multiple layers of the transcriptome. Together, these findings reveal that cocaine exposure reinforces an mA-defined regulatory RNA network, spanning coding and non-coding transcripts that is mechanistically linked to mA reader-dependent behavioral plasticity.
Structure matters: commensal lipopolysaccharide induces attenuated microglial activation and preserves neuronal integrity.
Mazziotti V, De Simone Carone L, Olmeo F … +4 more , Chiodo F, Silipo A, Molinaro A, Di Lorenzo F
Front Cell Neurosci · 2026 · PMID 42058701 · Full text
Lipopolysaccharides (LPSs) from Gram-negative bacteria are widely used to model neuroinflammation and . However, this paradigm assumes that all LPS chemotypes are uniformly pro-inflammatory, despite significant structur...
Lipopolysaccharides (LPSs) from Gram-negative bacteria are widely used to model neuroinflammation and . However, this paradigm assumes that all LPS chemotypes are uniformly pro-inflammatory, despite significant structural diversity between enterobacterial pathogens and gut-resident commensals. Whether microglia can discriminate among these chemotypes remains largely unexplored. We performed a comparative analysis of canonical LPS and commensal-derived LPS in murine (BV2) and human (HMC3) microglial cells. Pro-inflammatory mediators were quantified by ELISA, and TLR4-downstream signaling was assessed by western blotting. Conditioned media (CM) from LPS-treated BV2 and HMC3 cells was applied to PC12 neuronal cells to evaluate cell viability and differentiation by immunofluorescence. In BV2 microglial cells, LPS did not induce nitric oxide (NO) production or iNOS expression. In both BV2 and HMC3 cells, it failed to trigger pro-inflammatory cytokine release or TLR4 pathway activation. CM from -treated microglia disrupted MAP2 expression in PC12 neurons, whereas media from -treated microglia did not. Overall, our data argue that "LPS-induced neuroinflammation" is not a universal phenomenon, but a chemistry-dependent outcome shaped by specific LPS structures. This study therefore highlights the need to consider LPS structural diversity in neuroinflammation models, particularly in the context of gut-brain communication.
Purkinje cell-specific loss of Neurofascin and Ankyrin G causes disruption of axon initial segments, neurodegeneration, and cerebellar ataxia.
Shi Q, Taylor AM, Sell LB … +1 more , Bhat MA
Front Cell Neurosci · 2026 · PMID 42052621 · Full text
The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal polarity, yet the developmental roles of its core molecular components-Neurofascin 186 (NF186) and Ankyrin G (AnkG)-re...
The axon initial segment (AIS) is essential for initiating action potentials and maintaining neuronal polarity, yet the developmental roles of its core molecular components-Neurofascin 186 (NF186) and Ankyrin G (AnkG)-remain incompletely defined in cerebellar Purkinje cells. Here, we generated Purkinje cell-specific NF186 and AnkG single- and double-knockout mice to investigate how these adhesion and scaffolding proteins cooperatively regulate AIS formation, ion channel localization, synaptic targeting, and neuronal survival. We found that genetic ablation of either () or () disrupted assembly and maintenance of the AIS cytoskeleton, and that this defect was exacerbated by combined loss of both proteins during postnatal development. Other AIS-enriched proteins, including βIV Spectrin (βIVSpec), voltage-gated sodium (Na), and potassium (K1.2) channels, failed to properly localize to the AIS and progressively disintegrated between postnatal days 10 and 30. Notably, K1.2 clustering at the pinceau synapse was disrupted, and basket cell axons showed misaligned terminal organization, indicating defective inhibitory synapse innervation. By 2 months of age, degeneration of Purkinje cells was evident, accompanied by cerebellar dysfunction. Notably, ablation caused a progressive postnatal loss of NF186 at the AIS, whereas ablation resulted in much slower loss of AnkG at the AIS in Purkinje cells and closely phenocopied the severe AIS destabilization observed in double-knockout mice. In addition, our RNA-seq analysis revealed that Purkinje cell-specific loss of NF186 predominantly activated immune-inflammatory pathways; AnkG loss significantly disrupted neuronal developmental and metabolic processes; and the dual loss of NF186/AnkG produced transcriptional changes that were distinct from, and in part intermediate to, those observed in NF186 and AnkG single knockout. Collectively, our results show that NF186 and AnkG have complementary, non-redundant roles in establishing and maintaining the Purkinje cell AIS, and that their loss disrupts synaptic organization at the AIS. These findings advance our understanding of AIS development in cerebellar neurons and have implications for diseases involving AIS dysfunction, including cerebellar ataxia and demyelinating neuropathies.
Editorial: Reviews in cellular neuropathology.
Tozzi A, Deng C, Hermann DM
Front Cell Neurosci · 2026 · PMID 42052620 · Full text
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Presynaptic chloride-dependent regulation of spontaneous glutamate release in the rat medial preoptic nucleus.
Pérez-Del-Pozo M, Kuznetsova T, Johansson S … +1 more , Druzin M
Front Cell Neurosci · 2026 · PMID 42038341 · Full text
Neurosteroids and inhibitory neurotransmitters can modulate neurotransmitter release from presynaptic terminals, yet the mechanisms underlying such modulation remain unclear. In this study, we investigated how presynapti...
Neurosteroids and inhibitory neurotransmitters can modulate neurotransmitter release from presynaptic terminals, yet the mechanisms underlying such modulation remain unclear. In this study, we investigated how presynaptic glycine and GABAR-receptors (GlyRs and GABARs) regulate glutamate release onto neurons in the medial preoptic nucleus (MPN), a hypothalamic region critically involved in reproductive and social behaviors. Using patch-clamp recordings from mechanically dissociated MPN neurons with functionally preserved presynaptic terminals, we selectively examined local presynaptic effects of receptor activation. Both the neurosteroid allopregnanolone and the selective GABAR agonist muscimol consistently increased the frequency of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). This facilitation was sensitive to the GABAR-blocker picrotoxin, abolished by inhibition of sodium-potassium-chloride cotransporter 1 (NKCC1) or by the sodium-channel blocker tetrodotoxin, consistent with a mechanism involving depolarizing chloride efflux driven by a high intraterminal chloride ion concentration and subsequent sodium-dependent recruitment of presynaptic calcium channels. In contrast, activation of presynaptic GlyRs produced bidirectional effects on glutamate release: facilitation in some terminals and inhibition in others. We demonstrate that the inhibitory effect likely depends on low intraterminal chloride concentration maintained by the potassium-chloride cotransporter 2 (KCC2), which enables chloride influx and hyperpolarization upon GlyR activation. Consistent with this mechanism, pharmacological blockade of chloride extrusion abolished glycine-induced inhibition, and immunogold labeling revealed KCC2 presence in a subset of presynaptic terminals innervating MPN neurons. Together, these findings suggest functional presynaptic KCC2 in central neurons and identify presynaptic chloride homeostasis as a key determinant of synapse-specific modulation of glutamate release in the MPN.
Yellow cerebrospinal fluid in an extremely preterm infant: a case report.
Chen X, Li H, Li J … +6 more , Chen L, Liu X, Xie D, Chen Y, Yuan J, Tao E
Front Cell Neurosci · 2026 · PMID 42038340 · Full text
Although phototherapy has reduced the incidence of kernicterus in term infants, it remains a significant threat to extremely preterm infants due to their immature blood-brain barrier and frequent comorbidities such as se...
Although phototherapy has reduced the incidence of kernicterus in term infants, it remains a significant threat to extremely preterm infants due to their immature blood-brain barrier and frequent comorbidities such as sepsis. Current clinical practice relies on serum total bilirubin levels, which may not accurately reflect cerebral bilirubin exposure in this vulnerable population. This case report describes an extremely preterm infant (gestational age 28 1/7 weeks, birth weight 950 g) who developed visibly yellow cerebrospinal fluid (CSF) on the first day of life. Despite only minimal serum hyperbilirubinemia (4.4 mg/dL; ≈ 75.2 μmol/L), CSF bilirubin was markedly elevated at 10 mg/dL (≈ 171 μmol/L). The infant presented with respiratory distress syndrome and sepsis. Immediate intensive phototherapy was initiated, leading to the normalization of CSF bilirubin (3.6 mg/dL ≈ 61.5 μmol/L) within 4 days. Brain magnetic resonance imaging (MRI) and automated auditory brainstem response (AABR) performed at the corrected age of 4 months were both unremarkable. At the corrected age of 12 months, neurodevelopmental assessment using the Bayley Scales of Infant Development-III (BSID-III) showed scores within the normal range. This case illustrates that CSF bilirubin can serve as a sensitive early biomarker for identifying preterm infants at imminent risk for bilirubin neurotoxicity, particularly when serum bilirubin levels are misleadingly low. Targeted measurement of CSF bilirubin in selected high-risk infants, when a lumbar puncture is otherwise indicated, could enable more timely intervention and contribute to improved neurodevelopmental outcomes.
Mu-opioid and nociceptin receptors show divergent, cell-type-specific actions in the mesocorticolimbic reward system in opioid use disorder.
Allichon MC, Espinosa J, Cole RH … +3 more , Ko MC, Vanhoutte P, Joffe ME
Front Cell Neurosci · 2026 · PMID 42038339 · Full text
The mu-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOPR) are closely related yet functionally distinct modulators of rewards, motivation, and affect. Within the mesocorticolimbic system, including the...
The mu-opioid receptor (MOR) and the nociceptin/orphanin FQ receptor (NOPR) are closely related yet functionally distinct modulators of rewards, motivation, and affect. Within the mesocorticolimbic system, including the prefrontal cortex (PFC), the ventral tegmental area (VTA) and the nucleus accumbens (NAc), these receptors exhibit divergent, cell type-specific expression patterns that drive opposing behavioral outcomes. For example, MOR activation enhances rewards processing and reinforcement by facilitating dopamine transmission, whereas NOPR signaling in the VTA can reduce dopamine cell activity. In addition, MOR and NOPR are positioned within cortical circuits to preferentially reduce GABA and glutamate transmission, respectively. This review synthesizes current knowledge on how MOR and NOPR coordinate motivational and affective states through distinct neuronal populations across the mesocorticolimbic circuit. We also discuss emerging evidence for functional interactions between these systems and the therapeutic implications of pharmacological strategies targeting both receptors, including dual-acting MOR/NOPR ligands that enhance analgesic efficacy with reduced abuse liability. By integrating behavioral, molecular, and circuit-level findings, this synthesis aims to clarify how MOR and NOPR signaling jointly shape rewards and stress pathways, and provide insight into the development of safer and more effective treatments for opioid use disorders.
Sexual dimorphism and acute stress modulation of infralimbic-posterior hypothalamic synaptic transmission.
Rivera-Escobales Y, Hernández-Crispín DN, Pérez-Morales J … +2 more , Colón M, Porter JT
Front Cell Neurosci · 2026 · PMID 42038338 · Full text
Acute stress engages neural circuits that coordinate autonomic and neuroendocrine responses, including projections from the infralimbic cortex (IL) to the posterior hypothalamic nucleus (PH). Although both regions are ac...
Acute stress engages neural circuits that coordinate autonomic and neuroendocrine responses, including projections from the infralimbic cortex (IL) to the posterior hypothalamic nucleus (PH). Although both regions are activated during stress, the synaptic mechanisms underlying IL-to-PH communication remain poorly understood. Here, we combined optogenetics with whole-cell patch-clamp electrophysiology to determine how acute restraint stress alters excitatory synaptic transmission from IL to PH neurons in adult male and female rats. IL afferents formed functional glutamatergic synapses onto PH neurons in both sexes, characterized by short-term facilitation and a high AMPA/NMDA ratio. However, females exhibited smaller optically evoked excitatory postsynaptic currents (EPSCs) in response to single or burst stimulation across multiple holding potentials. NMDA receptor-mediated EPSCs and NMDAR-predominant spontaneous EPSCs also displayed sex differences, with females showing smaller and faster synaptic currents. When data were collapsed across sex, acute restraint stress enhanced NMDAR-mediated synaptic currents at IL-to-PH synapses while reducing the amplitude of NMDAR-predominant spontaneous EPSCs without altering their frequency. Together, these findings reveal sex-dependent differences in excitatory IL-to-PH synaptic signaling and suggest that acute stress preferentially modulates NMDAR-mediated transmission in this pathway. These results highlight dynamic postsynaptic mechanisms that shape prefrontal-hypothalamic communication during acute stress.
Cynanchum bungei Decne-derived extracellular vesicles alleviate cognitive impairment and pathological damage in Alzheimer's disease.
Hong R, Han J, Dong F … +5 more , Kalsoom UE, Cao C, Zhou A, Wu Q, Qu X
Front Cell Neurosci · 2026 · PMID 42038337 · Full text
INTRODUCTION: Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossi...
INTRODUCTION: Decne (CB) is known for its therapeutic benefits for neurodegenerative conditions as anti-inflammatory, antioxidant, and barrier significantly limits their potential advantages. Given the ability of crossing the barrier with minimal toxicity, extracellular vesicles derived from CB (CB-EVs) were utilized as an innovative approach to mitigate Alzheimer's disease (AD). METHODS: CB-EVs were isolated using gradient ultracentrifugation and identified via TEM imaging, nanoparticle tracking analysis, marker identification, and imaging system. Ten-month-old triple transgenic AD (3xTg-AD) mice received intravenous administration of CB-EVs at doses of 10 or 20 mg/kg every 3 days for the cognitive and pathological assessments. The human APP Swedish mutation transgenic SH-SY5Y cells were constructed as Aβ-induced neural damage model, and different concentrations of CB-EVs were added into medium to analyze its roles on cell viability, transcriptome changes, oxidative stress, and mitochondrial damage. RESULTS: CB-EVs exhibited standard morphological and molecular traits, accumulating in the cerebral cortex and hippocampus. Two months of CB-EVs treatment alleviated cognitive impairments, diminished Aβ plaque, reduced Tau protein hyperphosphorylation, and lessened neuronal loss in 3xTg-AD mice. In transgenic SH-SY5Y cells, CB-EVs improved cell viability, enhanced superoxide dismutase activity, downregulated oxidative stress related NUPR1 and CHOP expression, decreased reactive oxygen species, lipid peroxidation, and malondialdehyde levels, reduced mitochondrial damage. CONCLUSION: These results demonstrated that CB-EVs could protect neurons from oxidative stress, attenuate cognitive impairment and pathological damage in AD.
Intestinal inflammation promotes neuroinflammation and PD-associated nigrostriatal pathology independently of LRRK2 G2019S kinase activity.
Merchak AR, Herrick MK, Houser MC … +3 more , Keating CE, Chang J, Tansey MG
Front Cell Neurosci · 2026 · PMID 42038336 · Full text
INTRODUCTION: The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (...
INTRODUCTION: The pathogenesis of Parkinson's disease (PD) has been linked to environmental factors, toxins, genetics, and peripheral inflammation. Importantly, intestinal inflammation like that seen in Crohn's disease (CD) or food allergies has been implicated in risk for neurodegeneration and late-onset PD. Further, CD and PD share genetic risk factors including gain-of-function leucine-rich repeat kinase 2 () mutations. Here, we aim to better understand how intestinal inflammation synergizes with levels or kinase activation to promote neurodegeneration in young and old mice. METHODS: We utilized bacterial artificial chromosome (BAC) mice overexpressing wildtype mouse or mutant G2019S mouse and compared them with C57B6J mice at baseline and under conditions of intestinal inflammation using dextran sodium sulfate (DSS) colitis models. RESULTS: While our data revealed regulation of the brain inflammatory state by , we did not observe age-dependent selective vulnerability or protection in mouse lines in colitis protocols. Instead, DSS phenotypes were associated with increased nigrostriatal dysregulation in all genotypes independent of age. DISCUSSION: While mutations appear to influence the genesis of peripheral inflammation, our data suggest that activation due to a gain-of-function mutation does not exacerbate the effects of inflammation on nigrostriatal degeneration in this model.
Deletion of (Ca 1.2) in D1-expressing cells elicits divergent sex-specific effects on aversive and spatial memories.
Walsh JD, Scala-Chavez D, Lee AS … +2 more , Martínez-Rivera A, Rajadhyaksha AM
Front Cell Neurosci · 2026 · PMID 42028275 · Full text
Dopamine signaling is critical for cognitive and emotional regulation and is implicated in multiple neuropsychiatric disorders. One downstream effector of dopamine is the L-type calcium channel CaV1.2, encoded by the ris...
Dopamine signaling is critical for cognitive and emotional regulation and is implicated in multiple neuropsychiatric disorders. One downstream effector of dopamine is the L-type calcium channel CaV1.2, encoded by the risk gene . Genome-wide association studies have consistently linked single nucleotide polymorphisms to schizophrenia, bipolar disorder, and related conditions. We previously showed that homozygous deletion of in dopamine receptor 1 (D1)-expressing cells enhances remote (30 days post-training) contextual fear memory in male mice. Here, we extend these findings by examining sex- and gene dosage-dependent behavioral consequences of loss in D1 cells. We find a sex-dependent dissociation, where females show enhanced aversive memory up to 30 days post-training even with partial loss, whereas males require complete loss to show enhanced fear. In contrast, males show impaired spatial memory in the Water Y-maze following heterozygous or homozygous deletion, an effect not observed in females. Cue-associated fear memory was transiently elevated in females but unaffected in males. Locomotor activity was reduced in females during the initial minutes of testing, with no effects in males, while social interaction and anxiety-like behaviors were unchanged across groups. These findings indicate that Ca 1.2 signaling in D1-expressing cells differentially regulates aversive versus spatial memory in a sex-dependent manner, providing insight into how risk variants may contribute to sex-specific cognitive phenotype.
Microglial PD-1/PD-L1 axis in CNS demyelinating diseases: a dual immunoregulatory perspective.
Zhou M, Yao X, Liu L … +5 more , Gao Y, Chen W, Zheng K, Li H, Meng Q
Front Cell Neurosci · 2026 · PMID 42028274 · Full text
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) stand as archetypal autoimmune-mediated demyelinating diseases of the central nervous system (CNS). Emerging evidence highlights the dual immunom...
Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) stand as archetypal autoimmune-mediated demyelinating diseases of the central nervous system (CNS). Emerging evidence highlights the dual immunomodulatory functions of microglia in these diseases: on the one hand, they can secrete neurotoxic molecules that exacerbate neural damage; on the other hand, they are capable of releasing neuroprotective factors that promote tissue repair and enhance neuronal survival. This review dissects the programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) immune checkpoint axis, expressed on activated microglia, T cells, and other immune cells, as a pivotal rheostat of neuroinflammation. The binding of PD-1 to PD-L1 dampens immune cell activation and proliferation, curtails pro-inflammatory cytokine output, and is instrumental in preserving immune tolerance. In the context of chronic inflammation, persistent PD-1/PD-L1 signaling has been closely associated with the induction of T cell exhaustion than with direct apoptosis, though context-dependent effects on cell survival have been reported in certain experimental paradigms. Both microglia and the PD-1/PD-L1 axis are critically intertwined in the initiation and perpetuation of CNS demyelinating diseases. A more granular comprehension of their interplay will not only illuminate the molecular underpinnings of neuroinflammation and immune regulation in MS and NMOSD but also pave the way for crafting precision immunotherapies aimed at modulating microglial polarization. Here, we systematically review the dual immunomodulatory functions of the microglial PD-1/PD-L1 axis in these diseases and deliberate on the therapeutic prospects of targeting this pathway, thereby furnishing a conceptual framework for novel immune intervention strategies.
Correction: Discovery and optimization of tau targeted protein degraders enabled by patient induced pluripotent stem cells-derived neuronal models of tauopathy.
Silva MC, Nandi G, Donovan KA … +7 more , Cai Q, Berry BC, Nowak RP, Fischer ES, Gray NS, Ferguson FM, Haggarty SJ
Front Cell Neurosci · 2026 · PMID 42023052 · Full text
[This corrects the article DOI: 10.3389/fncel.2022.801179.].
[This corrects the article DOI: 10.3389/fncel.2022.801179.].
Neuronal differentiation and activity drive nucleocytoplasmic shuttling of the intellectual disability kinase TLK2.
Nuhu-Soso L, Denton H, Goffin DL … +2 more , Hahn I, Evans GJO
Front Cell Neurosci · 2026 · PMID 42023051 · Full text
INTRODUCTION: Autosomal dominant intellectual developmental disorder 57 (MRD57) is a rare neurodevelopmental disorder characterised by delayed language and psychomotor development, intellectual disability, hypotonia, gas...
INTRODUCTION: Autosomal dominant intellectual developmental disorder 57 (MRD57) is a rare neurodevelopmental disorder characterised by delayed language and psychomotor development, intellectual disability, hypotonia, gastrointestinal issues and facial dysmorphia. It is linked to genetic mutations in the serine/threonine kinase TLK2, which generally cause haploinsufficiency. TLK2 is an established cell cycle regulator that has been extensively studied in mitotic cells. It is upregulated in cancers, driving tumour growth, however, the role of TLK2 in postmitotic neurons is not understood. We therefore aimed to determine where TLK2 is expressed in the brain and its subcellular localisation during neuronal differentiation. METHODS: We analysed TLK2 transcript or protein expression and localisation in public RNAseq datasets, mouse brain sections, and a rat neuroblastoma cell line model of neuronal differentiation. RESULTS: Human and mouse brain transcriptomic data revealed splice variant diversity in the N-terminus of TLK2, which contains its nuclear localisation sequence (NLS). Using splice-specific in situ hybridisation probes, we observed expression of TLK2 transcripts that contain and lack the NLS in the mouse hippocampus and cerebellum. Surprisingly, TLK2 protein was predominantly cytoplasmic in the adult mouse brain. Similarly, in rat neuroblastoma cells, we found that neuronal differentiation enhances a cytoplasmic pool of TLK2 by two mechanisms: nuclear export of full length TLK2 and increased expression of TLK2 splice variants lacking the NLS. Finally, acute stimuli that mimic synaptic activity were sufficient to elicit nuclear export of TLK2. DISCUSSION: Our data highlight a previously unrecognised role of cytoplasmic TLK2 in neurons and future studies should determine how the loss of TLK2 activity in MRD57 impacts cytoplasmic TLK2 substrates in the developing and mature brain.
From mice to clinical relevance: humanizing neuroscience with human-based model systems.
Bak AV, van Loo KMJ, Kronenberg-Versteeg D … +1 more , Koch H
Front Cell Neurosci · 2026 · PMID 42004644 · Full text
Preclinical research in neuroscience has traditionally relied on animal models to investigate disease mechanisms and develop new therapeutic strategies. While these models are valuable to gain mechanistic insights, their...
Preclinical research in neuroscience has traditionally relied on animal models to investigate disease mechanisms and develop new therapeutic strategies. While these models are valuable to gain mechanistic insights, their translational power remains limited due to interspecific differences and, hence, frequent failures in clinical translation. The uniqueness of the human brain calls for alternative approaches in neuroscientific research that more faithfully capture human physiology and pathology. In recent years, a variety of human-based model systems have emerged, ranging from dissociated neuronal cultures and stem cell-derived platforms, including organoids, to micro-engineered devices and human brain slice approaches. Each model offers distinct advantages and limitations in recapitulating neural circuits, disease mechanisms, and therapeutic responses. In this review, we critically discuss the merits and drawbacks of animal models, outline the historic development and current applications of human-based systems, and highlight their potential to complement or replace animal-based models. We further explore current challenges in human brain research, including human variability, technical challenges, as well as ethical considerations and regulatory hurdles. Together, these advances represent a shift toward more predictive, human, and ethically responsible neuroscientific research that could aid in decreasing the translational gap.
"Mind the Gap"-enlarged perivascular spaces as a potential magnetic resonance imaging biomarker of impaired glymphatic clearance in brain disorders.
Kirsch CF, Herb M, Verma G … +1 more , Balchandani P
Front Cell Neurosci · 2026 · PMID 41993675 · Full text
The abundant capillary network penetrating the brain parenchyma is surrounded by potential tubular, fluid-filled regions referred to as perivascular spaces (PVSs). PVSs have a unique and complex history and are believed...
The abundant capillary network penetrating the brain parenchyma is surrounded by potential tubular, fluid-filled regions referred to as perivascular spaces (PVSs). PVSs have a unique and complex history and are believed to act as a pathway for the drainage of waste products from brain interstitial and cerebrospinal fluid (CSF) as part of the glymphatic clearance system. The unique perivascular "gap" spaces are eponymously linked to Virchow and Robin, who argued vigorously in the 1800s over PVSs' exact location and physiology. Currently, debates are ongoing regarding whether PVSs are predominantly periarteriolar, perivenular, or both and how they aid in clearing fluids from the brain parenchyma. In neurodevelopmental, neuropsychiatric, and neuropathological conditions, PVS can enlarge, a phenomenon referred to as enlarged perivascular spaces (ePVSs), which are identifiable on magnetic resonance imaging (MRI), with improved detection and resolution at higher magnetic field strengths. Quantification of ePVS enlargement on MRI using artificial intelligence (AI) imaging algorithms may serve as a potential non-invasive imaging biomarker for impaired glymphatic clearance and brain disorders. This mini-review presents the historical background and pathophysiology of PVSs and ePVSs, current debates regarding their exact location, their potential as neuroimaging biomarkers, and how AI may aid in ePVS quantification.
Utilizing a culture system for horizontal cells to study neural circuit assembly in the developing mouse retina.
Perez RM, Park YH, Singh A … +9 more , Todora C, Mattos MF, Becerril D, Venkatraman R, Hirano AA, Brecha NC, Ratnapriya R, Frankfort BJ, Zuniga-Sanchez E
Front Cell Neurosci · 2026 · PMID 41993674 · Full text
The precise wiring of the nervous system relies on neurons extending their processes at the right time and place to find their appropriate synaptic partner. The mechanisms that determine when and where neurons extend the...
The precise wiring of the nervous system relies on neurons extending their processes at the right time and place to find their appropriate synaptic partner. The mechanisms that determine when and where neurons extend their neurites during synaptogenesis remains a central question in the field. In the present study, we used a cell culture system coupled with live imaging to investigate the wiring mechanisms in the developing mouse retina. We focused on horizontal cells which are a class of interneurons in the outer mouse retina known to synapse selectively to the distinct types of photoreceptors. Previous research has shown horizontal cells extend their neurites and make connections to their respective photoreceptor partner in a temporal- and spatial-dependent manner. However, the mechanisms responsible for their selective wiring to photoreceptors during development remains poorly understood. To answer this question, we developed a horizontal cell culture system to investigate the cellular mechanisms responsible for neurite outgrowth during circuit assembly. Our data shows cultured horizontal cells extend neurites with a similar morphology as . Moreover, neurite extension of horizontal cells is limited to early developmental stages as young mice extend more complex processes compared to those from adolescent retinas. We also found that horizontal cells, unlike retinal ganglion cells, do not extend neurites when cultured alone and require other retinal neurons to promote neurite outgrowth. In summary, we established a horizontal cell culture system that can be used to decipher the mechanisms involved in neural circuit assembly of the mouse retina.
Contribution of proprioceptors in the mesencephalic trigeminal nucleus and their surrounding astrocytes to acidic saline-induced chronic jaw muscle pain in rodents.
Yamada M, Verdier D, Kolta A
Front Cell Neurosci · 2026 · PMID 41993673 · Full text
INTRODUCTION: Chronic jaw muscle pain is a common clinical condition whose etiology remains ill-defined. Using acidic saline injections into the masseter muscle to mimic it, we examined the hypothesis that hyperexcitabil...
INTRODUCTION: Chronic jaw muscle pain is a common clinical condition whose etiology remains ill-defined. Using acidic saline injections into the masseter muscle to mimic it, we examined the hypothesis that hyperexcitability of jaw closing muscles spindle afferents (MSA) that have previously been observed in this model result from neuron glia interactions in the trigeminal mesencephalic nucleus (NVmes) lead to activation of nociceptive pathways. METHODS: This was assessed using whole-cell patch-clamp recordings from NVmes neurons combined to pharmacological and astrocytic optogenetic stimulations and immunohistochemistry against cFos in the ventrolateral pole of the subnucleus interpolaris/caudalis transition region (vl-Vi/Vc), and GFAP in vl-Vi/Vc and NVmes regions in rats and mice. RESULTS: Acidic saline injection into the masseter muscle led to increases in: (1) cFos expression in vl-Vi/Vc at 9 days after the injection, (2) reactivity of astrocytes in NVmes, and (3) Excitability of NVmes neurons that manifested spontaneously or in response to astrocytic stimulation. This increased activity is thought to result from the release of the astrocytic Ca-binding protein S100β, since it was not observed in S100β knock-out mice, which also did not show increased expression of cFos in vl-Vi/Vc, despite showing increased reactivity of NVmes astrocytes. DISCUSSION: These findings suggest that acidic saline injection into the masseter muscles induced long-term activation of astrocytes in the NVmes and promoted ectopic firing of NVmes neurons via astrocyte-released S100β, and subsequent activation of nociceptive pathways.
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