IntroductionCerebellar malignant glioma is an extremely rare tumor, and its clinicopathological and molecular features remain unclear.MethodsThe clinical course, radiological findings, histopathology, and molecular characteristics of 11 adult patients (23–83 years; median: 75 years) with cerebellar malignant glioma who were treated between 2000 and 2024 were reviewed.ResultsThe primary site of the lesions was the cerebellar vermis in 4, cerebellar hemispheres in 5, and cerebellopontine angle in 2 patients. Perifocal edema was obscure in all but 2 patients. Considering the clinical information, and neuroimaging characteristics, the initial preoperative differential diagnoses were metastatic brain tumor in 3, malignant glioma in 3, ependymoma in 2, and malignant lymphoma, schwannoma, and pilocytic astrocytoma in 1 patient each. Ten patients underwent excision surgery, and 1 patient underwent biopsy. In the 2 patients in whom malignant glioma was strongly suspected before surgery, photodynamic therapy was performed intraoperatively. Initial pathological analysis showed that 8 patients had grade 4 glioma, and 3 patients had grade 2/3 glioma. The patient with grade 3 astrocytoma subsequently experienced recurrence with histological progression to grade 4. Isocitrate dehydrogenase 1 was wildtype in all 7 tested patients. The tumor tissues demonstrated heterogeneous histopathological features, including oligodendroglial, pilocytic, and giant cell-like components, in addition to the typical characteristics of glioblastoma. Notably, cerebellar infiltration of tumor cells was also observed. The tumors of 4 patients also had piloid features, and required differentiation between glioblastoma and high-grade glioma with piloid features (HGAP). Of the 9 patients who experienced recurrence, 4 demonstrated local recurrence, whereas the other 5 demonstrated distant or disseminated recurrence. The median overall survival was 29.0 months for all patients, and 19.5 months when limited to patients with grade 4 glioma including the patient with histological progression.ConclusionCerebellar malignant gliomas demonstrate considerable heterogeneity regarding their imaging, histopathology, and molecular profiles. Accurate diagnosis often requires integrated molecular analyses, including DNA methylation profiling. The identification of rare variants, such as HGAP, is essential for the appropriate diagnosis and management of cerebellar malignant gliomas.
Neuropathic pain maintenance often becomes autonomous of peripheral input once central sensitization is established. We hypothesize that perineuronal nets (PNNs)—extracellular-matrix condensates that, in the spinal dorsal horn, preferentially enwrap lamina I projection neurons—may function as active regulators of postsynaptic inhibitory efficacy, rather than merely passive physical scaffolds. We frame this as a two-cell circuit in which a PV+ interneuron provides the presynaptic gatekeeping input and a PNN-enwrapped lamina I projection neuron constitutes the postsynaptic site of KCC2 loss. Throughout, we use “molecular brake” for the PTPσ-dependent biochemical mechanism and “gatekeeper” for the circuit-level inhibitory function. In this hypothesis-and-theory article, we propose that, by physically restricting neurotrophin diffusion and by maintaining chondroitin-sulfate proteoglycan (CSPG)–protein tyrosine phosphatase sigma (PTPσ)-dependent dephosphorylation of tropomyosin receptor kinase B (TrkB), intact PNNs could preferentially restrain the phospholipase Cγ1 (PLCγ1)–calpain arm while sparing extracellular signal-regulated kinase (ERK)/Akt trophic signaling. Peripheral nerve injury (PNI)-induced PNN degradation could relieve this putative molecular brake; reduced PTPσ-dependent dephosphorylation may then amplify or prolong basal and brain-derived neurotrophic factor (BDNF)-dependent TrkB-PLCγ1 signaling, contributing to downregulation of the K+ –Cl− cotransporter 2 (KCC2) and to a depolarizing shift in the GABA type A (GABA_A)/glycine receptor reversal potential that weakens inhibitory transmission. We explicitly distinguish established findings from hypothetical steps, classify each component of the proposed PNN–PTPσ–TrkB–KCC2 pathway by level of evidence, and formulate falsifiable predictions. We discuss PNN stabilization and KCC2 enhancement as translationally relevant strategies; we discuss the PTPσ inhibitor intracellular sigma peptide (ISP) primarily as an experimental tool—and as a potentially double-edged modulator of TrkB signaling—rather than as a predicted analgesic; ISP is not listed among the therapeutic directions of this model. The proposed convergence of presynaptic (PV–SK) and postsynaptic (KCC2) mechanisms is presented as a circuit-level hypothesis that has not been demonstrated within a single cell population. Finally, we discuss sex-specific divergence. Direct validation of this model in peripheral neuropathic pain models remains an urgent priority.
BackgroundSpinal cord injury (SCI) results in permanent functional deficits, and effective neurorehabilitative strategies remain an unmet clinical need. Neurotrophin-3 (NT-3) has emerged as a candidate therapeutic agent, but its molecular mechanisms in promoting functional recovery are incompletely understood.MethodsA rat SCI model was established. Motor function recovery was assessed using the Basso-Beattie-Bresnahan (BBB) score, and related protein expression was detected via western blotting and immunofluorescence. In vitro, an oxygen–glucose deprivation (OGD) model in primary oligodendrocytes was used to simulate injury. Receptor knockdown, pathway inhibitors [3-methyladenine (3-MA), rapamycin (Rap)], a ubiquitination inhibitor (PYR41), and an endocytosis inhibitor (cytochalasin B), combined with co-immunoprecipitation, immunofluorescence, and western blot analysis, were employed to systematically investigate the temporal regulation of autophagy by NT-3, the involved signaling pathways (AMPK/mTOR and PI3K/AKT/mTOR), and the ubiquitination-dependent endocytic degradation of the P75 neurotrophin receptor (P75NTR).ResultsIn vivo, endogenous NT-3 increased after SCI, and exogenous NT-3 significantly improved BBB scores at days 3 and 7, reduced oligodendrocyte apoptosis, and increased PLP1 expression at day 7. Mechanistically, NT-3 bidirectionally regulated autophagy: acute phase (day 3 in vivo/3 h in vitro) via P75NTR/AMPK/mTOR, and subacute phase (day 7 in vivo/12 h in vitro) via TrkC/PI3K/AKT/mTOR. This receptor switch was driven by NT-3-induced ubiquitination-dependent endocytosis and degradation of P75NTR. These molecular changes correlated with enhanced functional recovery and myelin repair.ConclusionNT-3 induces ubiquitination-dependent endocytic degradation of P75NTR, enabling a temporal switch from P75NTR/AMPK/mTOR to TrkC/PI3K/AKT/mTOR signaling, resulting in a fine-tuned, bidirectional regulation of oligodendrocyte autophagy after SCI. This dynamic regulation is a key mechanism by which NT-3 sustains oligodendrocyte survival, promotes myelin repair, and facilitates functional recovery.
BackgroundAscending somatosensory pathways are formed before birth and refined in the early postnatal stages through activity-dependent mechanisms. In this context, the electrophysiological maturation of thalamocortical (TC) neurons is crucial to tune growing circuitry and ensure the fidelity of information processing. Accordingly, perturbations in ionic homeostasis during this vulnerable period might result in neurodevelopmental disorders. Encoded by Kcnq2 and Kcnq3, Kv7 or M-channels primarily assemble into hetero-tetramers under physiological conditions to mediate a subthreshold potassium current, termed M-current (IM), that regulates intrinsic excitability and neuronal firing signatures. Yet, how partial or complete absence of Kcnq3 subunits affects active and passive properties of developing TC neurons has hitherto not been fully elucidated.MethodsHere, by performing patch-clamp recordings in the mouse ventrobasal thalamic complex (VB), we provide a comprehensive electrophysiological characterization of the IM during postnatal development. We used transgenic mice carrying Kcnq3 mutations, corresponding to human orthologous variants associated with childhood forms of epilepsy, to investigate the impact of Kcnq3 full deletion and haploinsufficiency on the membrane properties and specific firing pattern of TC neurons. Furthermore, we determined the differential contribution of KCNQ2 and KCNQ3 channels to IM generation by expressing the human gene plasmids in Chinese hamster ovary (CHO) cells at defined subunit ratios.ResultsPharmacological modulation with the Kcnq opener retigabine (RTG) revealed a gradual increase in IM magnitude during the first 30 postnatal days, whereas relative Kcnq2 and Kcnq3 transcripts remained unchanged across development. In the partial or complete absence of Kcnq3 channels, TC neurons exhibited hyperexcitability, characterized by enhanced burst firing and altered single action potential waveform. In accordance with these findings, equimolar KCNQ2/KCNQ3 expression evoked larger currents compared to either KCNQ2-dominant or KCNQ3-dominant subunit compositions.ConclusionOur results suggest a central role for the Kcnq3 channels in stabilizing the membrane properties and firing mode of developing TC neurons, thus ensuring the faithful transmission of peripheral input to the cerebral cortex.
IntroductionThe aim of the present study was to investigate the mechanism by which lncR-AK158273 regulates autophagy in lipopolysaccharide (LPS)-induced neuroinflammation cognitive impairment (LPS-NCI).MethodsLPS was used to establish a mouse of neuroinflammation‑mediated cognitive dysfunction. Cognitive deficits in the LPS‑NCI model were assessed using the new-object recognition test and Y maze test. Immunohistochemistry and immunofluorescence were performed to evaluate neuronal injury and the expression of CD11b, phosphorylated (p)-tau, and total tau. ELISA was used to quantify the levels of TNF-α and IL-6. RT-qPCR and western blotting were applied to measure the mRNA expression of STK4 and lncR-AK158273, as well as the protein levels of Mst1 and autophagy-related proteins. In addition, si-lncR-AK158273 or pcDNA-lncRNA-AK158273 was transfected into LPS‑stimulated BV2 cells to explore the function of this lncRNA in autophagy. Autophagosomes were visualized by transmission electron microscopy. Autophagic flux was determined using mRFP-GFP-LC3 fluorescence tracing with chloroquine (CQ) treatment to block lysosomal degradation.ResultsThe results showed that LPS markedly elevated the protein levels of CD11b, TNF-α, IL-6, p-tau, Aβ1–42, and P62, while reduing Beclin-1 expression and the LC3II/LC3I ratio, thereby suppressing autophagy in both LPS‑NCI mice and LPS-stimulated BV2 cells (P < 0.05). Futhermore, lncR-AK158273 and STK4(Mst1) were significantly upregulated in LPS‑NCI mice and LPS-treated BV2 cells. Follow-up experiments verified that lncR-AK158273 upregulates Mst1 expression upon LPS stimulation. Moreover, lncR-AK158273 suppressed LPS‑triggered microglial autophagy by increasing Mst1 level.DiscussionlncR-AK158273 may inhibit microglial autograph via upregulation of Mst1 expression during LPS-induced neuroinflammation.
