CNS Neuroscience & Therapeutics最新文献

Background: Temporal lobe epilepsy (TLE) is characterized by synaptic dysfunction for which targeted therapies are lacking. Hydroxysteroid dehydrogenase-like 2 (HSDL2) was previously identified as a potential regulator in TLE, but its precise functional and mechanistic role remained unexplored.

Methods: We compared HSDL2 protein expression in cortical tissues from patients with drug-resistant TLE and a kainic acid (KA)-induced mouse model via western blotting. Cellular localization was determined by immunofluorescence co-staining with neuronal (NeuN and PSD95), astrocytic (GFAP), and microglial (IBA1) markers. Adeno-associated virus (AAV) vectors were used to overexpress or knock down HSDL2 in the mouse hippocampus, followed by behavioral seizure assessments using pentylenetetrazol (PTZ) and chronic monitoring of spontaneous recurrent seizures (SRS). Underlying mechanisms were investigated through protein-protein interaction, patch-clamp electrophysiology, and quantitative co-immunoprecipitation.

Results: HSDL2 was significantly upregulated in both human TLE foci and the KA-induced epileptic mouse brain. It was localized to both neurons and astrocytes. In vivo, HSDL2 overexpression prolonged the latency to PTZ-induced seizures and reduced SRS frequency, whereas its knockdown exacerbated seizure severity and duration. Mechanistically, HSDL2 enhanced the membrane localization of postsynaptic density protein 95 (PSD95) and promoted its phosphorylation. This modification disrupted the physical interaction between PSD95 and the N-methyl-D-aspartate receptor (NMDAR) NR2B and NR2A subunits, leading to a reduction in NMDAR-mediated synaptic currents and neuronal hyperexcitability.

Conclusions: Our findings identify HSDL2 as a novel endogenous antiseizure protein that confers protection in epilepsy by modulating synaptic excitability. Specifically, HSDL2 regulates the PSD95-NMDAR complex through post-translational modification of PSD95, thereby inhibiting excessive NMDAR activity. Its therapeutic modulation may offer a strategy for drug development in TLE.

Aims: This study aimed to explore the effects of TC-2153, the STriatal Enriched Tyrosine Phosphatase (STEP) inhibitor, on Long-Term Depression (LTD) and basal synaptic transmission in hippocampal slices.

Methods: Extracellular field potentials were recorded in the CA1 area of the hippocampal slices. LTD was induced by low-frequency stimulation and by metabotropic glutamate receptor stimulation. The activity of STEP was measured in hippocampal slices and in SH-SY5Y cell culture by a colorimetric assay using p-nitrophenol as a substrate. To evaluate adenosine levels, adenosine was extracted from hippocampal slices homogenates and measured by HPLC.

Results: TC-2153 3 μM, applied to the slices one hour before and then along the electrophysiological recordings, blocked both forms of LTD. When hippocampal slices were treated with TC-2153 for shorter periods, 10-20 min, TC-2153 reduced synaptic transmission and increased STEP activity with an adenosine A1 receptor-dependent mechanism. Consistently, we found that TC-2153 increased adenosine levels in hippocampal slices. The increase in STEP activity after brief TC-2153 treatment has been confirmed in SH-SY5Y cells.

Conclusion: Our study confirms the role of STEP in LTD and reveals a new mechanism of action for TC-2153. The unexpected adenosine-dependent activation of STEP by TC-2153 has significant implications for both basic research and potential therapeutic applications.

Background: The glymphatic system is a perivascular cerebrospinal fluid (CSF)-interstitial fluid (ISF) exchange pathway that supports brain homeostasis by clearing metabolic waste and neurotoxic proteins. Across central nervous system diseases, converging evidence indicates that glymphatic dysfunction represents a shared pathophysiological axis linking vascular, astroglial, inflammatory, and sleep-related disturbances to impaired solute clearance.

Results and conclusion: In this review, we synthesize mechanistic and clinical evidence for glymphatic impairment in acute brain injury (ischemic and hemorrhagic stroke, traumatic brain injury) and chronic neurological disorders (Alzheimer's disease, Parkinson's disease, cerebral small vessel disease, multiple sclerosis, idiopathic normal pressure hydrocephalus, idiopathic intracranial hypertension, epilepsy, and headache disorders). Major mechanisms include (i) aquaporin-4 (AQP4) depolarization/mislocalization at astrocytic endfeet, reducing perivascular water transport; (ii) perivascular space compression or obstruction from cytotoxic/vasogenic edema, blood-derived products, protein aggregates, or altered extracellular matrix; (iii) loss of arterial pulsatility and vascular stiffening, weakening the driving forces for convective exchange; (iv) blood-brain barrier disruption and neuroinflammation, which remodel perivascular architecture and amplify clearance failure; and (v) sleep and autonomic dysregulation, including altered noradrenergic tone, which suppresses glymphatic activity during periods when clearance is normally maximal. Clinically, glymphatic dysfunction can be probed using diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS), contrast-enhanced MRI approaches, and structural surrogates such as enlarged perivascular spaces, with emerging associations to cognition, mood, and disease severity. Finally, we discuss translational strategies aimed at restoring clearance, including sleep/circadian optimization, vascular risk control, anti-inflammatory approaches, AQP4- and TRPV4-oriented targets, and neuromodulation. Mechanism-guided, standardized imaging and longitudinal interventional studies are needed to establish glymphatic biomarkers as actionable therapeutic and prognostic tools.

Background: Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) significantly improves motor symptoms in advanced Parkinson's disease (PD). However, the perioperative "microlesion effect" (MLE) is often associated with cognitive dysfunction, notably declines in verbal fluency (VFT). The dynamic neural mechanisms underlying cognitive network impairment during the MLE phase and functional reorganization following DBS stimulation remain poorly understood.

Aims and methods: This study employed longitudinal task-based functional near-infrared spectroscopy (fNIRS) to prospectively track 20 PD patients undergoing bilateral STN-DBS. To effectively disentangle the effects of natural surgical recovery from those specific to electrical stimulation, data were collected at four critical time points: 1 day preoperatively (Pre, T0), 7 days postoperatively (MLE phase, Post, T1), 1 month postoperatively with stimulation off (endpoint of natural recovery, Off, T2), and 1 week after stimulation onset (T3). VFT behavioral performance and global cognitive function (MoCA) were assessed concurrently. Hemodynamic signals from fNIRS were analyzed to examine activation changes in the prefrontal-temporal cortices. Furthermore, graph theory analysis was applied to quantify the dynamic evolution of topological properties within the core cognitive and motor networks.

Results: VFT scores dropped during MLE (8.70 ± 2.30 to 5.70 ± 1.78, p < 0.01), partially recovering post-stimulation (8.15 ± 2.48, p < 0.05). MoCA scores also declined in MLE (25.40 ± 1.27 to 21.95 ± 1.10, p < 0.001). Neuroimaging showed activated channels decreased from 8 preoperatively to 2 during MLE (FDR-corrected), followed by reactivation to 12 channels after stimulation, particularly in dorsolateral/ventrolateral prefrontal regions. Between-group comparisons revealed enhanced activation in right DLPFC (Ch6), right SMA (Ch19), and left VLPFC (Ch47) after stimulation versus MLE (all p < 0.05, FDR-corrected).

Conclusion: Our findings indicate that MLE-related cognitive decline may stem from acute local network disruption, while DBS can promote functional reorganization of cognitive networks. fNIRS proves to be a valuable tool for monitoring DBS-induced neuroplasticity in PD.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory impairment, posing significant challenges to affected individuals, their families, and healthcare systems globally. With projections indicating that the prevalence of AD could escalate to 152 million cases by 2050, there is an urgent need to elucidate the underlying mechanisms driving this condition. Additionally, developing effective diagnostic tools to aid in its early detection and management is crucial.

Methods: In this study, we utilized a combination of Mendelian randomization and advanced machine learning techniques to analyze transcriptomic data from five distinct cohorts of Alzheimer's Disease (AD) patients. After addressing batch effects, we identified differentially expressed genes (DEGs) between the AD and control groups. Mendelian randomization analysis was conducted to assess the causal relationships between DEGs and AD risk. A Venn diagram was subsequently used to identify genes associated with cholesterol metabolism from the screened gene set. The shared DEGs were subjected to functional enrichment analyses. Furthermore, immune analysis was quantified using Gene Set Enrichment Analysis (GSEA). A diagnostic model for AD was developed by evaluating 113 combinations of 12 machine learning algorithms with 10-fold cross-validation on the training datasets, followed by external validation on test datasets. Finally, immunofluorescence staining was performed on mouse brain slices to verify the expression level of KLHL21.

Results: Our analyses identified a substantial number of differentially expressed genes (DEGs) demonstrating significant differences between Alzheimer's disease (AD) patients and control groups. Among these, we identified 29 genes associated with AD, with 21 of them linked to cholesterol metabolism, highlighting its pivotal role in the disease's pathogenesis. From this set, we developed a robust 8-gene diagnostic signature (comprising CHSY1, FIBP, DHCR24, HVCN1, KIFAP3, KLHL21, LETMD1, and SLC25A29), which outperformed existing AD diagnostic models in both training and testing cohorts. Additionally, complementary animal experiments were conducted to validate the biological relevance of these genes, further elucidating their roles in AD pathology.

Conclusions: Our research identified critical genes and proposed novel pathways for early diagnosis and potential therapeutic interventions, paving the way for enhanced clinical applications in Alzheimer's disease management.

Background: Alzheimer's disease (AD), the most common form of dementia, lacks effective disease-modifying treatments. Rapamycin, an mTOR inhibitor with immunomodulatory properties, may mitigate AD pathology by restoring microglial functions.

Methods: Rapamycin was orally administered to 2-month-old 5xFAD and hAPP^NL.

Results: Rapamycin treatment reduced the cerebral Aβ plaque burden, alleviated dystrophic neurites, suppressed glial hyperactivation, and increased plaque-associated microglial density in both mouse models, with more pronounced effects in female mice. These pathological improvements were associated with attenuated deficits in hippocampal-dependent memory tasks (spontaneous alternation in the Y-maze and contextual fear conditioning tasks). Mechanistically, rapamycin enhances microglial lysosomal degradation, promotes lipid droplet clearance in BV2 cells, and increases Aβ phagocytic clearance in primary microglial cells.

Conclusions: Our findings suggest that rapamycin reduces amyloid pathology and associated behavioral deficits in AD mice, an effect associated with enhanced microglial lysosomal activity and Aβ clearance, highlighting its therapeutic potential in AD treatment.

Background: Forty Hz light flicker has shown promise in mitigating cognitive impairments, though its mechanisms remain unclear.

Aims: This study aimed to use perioperative neurocognitive dysfunction (PND) as a unique model of neural damage to provide a broader understanding of the neural mechanisms underlying the cognitive improvements associated with 40 Hz visual stimulation and offer new insights into the clinical application of PND treatment.

Materials and methods: Postoperative cognitive function was assessed through behavioral tests. Male and female mice received various visual light flicker stimuli, including 40 Hz, random, continuous, or no light. Local field potentials were recorded from the hippocampal dentate gyrus (DG) and primary visual cortex.

Results: Our results show that among the stimuli, only the 40 Hz flicker improved cognitive function, impaired by anesthesia or surgery. Intraoperative 40 Hz stimulation activated the primary visual cortex and was correlated with enhanced gamma coherence between this region and the hippocampal DG, a coherence that surgery itself notably reduced. This preserved functional connectivity. Additionally, hippocampal DG activity was enhanced, particularly in the gamma frequency range.

Conclusion: Our results suggest that 40 Hz flicker mitigates anesthesia/surgery-induced cognitive deficits, potentially through modulating gamma coherence between the visual cortex and hippocampus. These findings provide insights into PND prevention and the neural mechanisms underlying 40 Hz-induced cognitive benefits.

Background: Acid sphingomyelinase (ASM), encoded by SMPD1, regulates sphingolipid metabolism and has been implicated in tumor progression and immune modulation. However, its role in glioma remains poorly defined.

Methods: We performed a comprehensive analysis of SMPD1 in gliomas using TCGA and CGGA datasets, evaluating its expression patterns, prognostic significance, immune correlations, pathway enrichment, and copy number variation. Using qRT-PCR, we validated in vitro the effect of SMPD1 expression on macrophage polarization. Immunofluorescence staining was used to assess the levels of ASM of clinical samples and its correlation with tumor-associated macrophages. The functional role of SMPD1 was further validated in vivo.

Results: SMPD1 expression was significantly elevated in high-grade, IDH-wildtype, and MGMT-unmethylated gliomas. High SMPD1 levels were associated with poor prognosis and served as an independent prognostic factor. Tumors with elevated SMPD1 showed increased infiltration of regulatory T cells and M0/M2 macrophages. SMPD1 expression correlated with multiple immune cell markers and immune checkpoint molecules. Cell-based experiments showed that knocking out or inhibiting ASM drives macrophages toward an M1 phenotype while suppressing M2 polarization. Immunofluorescence analysis confirmed upregulation of ASM protein in high-grade, IDH-wildtype gliomas, with a strong positive correlation with CD163 expression in clinical samples. In vivo, inhibition of SMPD1 significantly suppressed glioma growth.

Conclusion: SMPD1 is a potential biomarker and therapeutic target in gliomas. Its upregulation may contribute to the formation of an immunosuppressive microenvironment and promote tumor progression, highlighting its potential relevance in glioma immunotherapy.

Background and aims: The aggregation of α-synuclein (α-syn) is a central event in Parkinson's disease (PD) pathogenesis. However, the cellular factors that initiate and accelerate the process are not fully understood. Synaptogyrin-3 (SYNGR3) is a synaptic vesicle protein whose role in α-syn pathology remains unexplored. This study investigated whether SYNGR3 is a key factor triggering the pathological process of PD.

Methods: This study investigated the expression of SYNGR3 in the brains of transgenic A53T α-syn mutant mouse line M83 (TgA53T) PD model mice using Western blot. The direct interaction between SYNGR3 and α-syn was assessed by GST pull-down assays. This study examined the effect of SYNGR3 on α-syn aggregation kinetics and fibril stability in vitro through the thioflavin T (Th T) assays and proteinase K (PK) digestion. By overexpressing or knocking down SYNGR3 in HEK-293 cells stably transfected with α-syn, primary neurons, and TgA53T mice, the effects of enhanced or deficient function of SYNGR3 on α-syn pathology, synaptic integrity, mitochondrial function, and motor behavior were evaluated.

Results: SYNGR3 levels were significantly elevated in an age-dependent manner in the striatum of TgA53T mice. The study found that SYNGR3 directly interacts with the central region of α-syn and accelerates its aggregation into fibrils that are more resistant to PK digestion. Overexpression of SYNGR3 exacerbated α-syn aggregation, synaptic protein loss, mitochondrial dysfunction, and apoptosis in cellular models. In vivo, SYNGR3 intensified α-syn pathology, dopaminergic neurodegeneration, and PD-like motor deficits. Conversely, knockdown of SYNGR3 effectively alleviated these pathological and behavioral impairments.

Conclusion: This study identifies SYNGR3 as a novel and critical promoter of α-syn aggregation and neurotoxicity. These findings establish SYNGR3 as a key contributor to PD pathogenesis and highlight its potential as a therapeutic target for intervention.

Background: Approximately 30% of epilepsy patients still develop drug resistance after standard antiepileptic treatment. Therefore, there is an urgent need to identify new drug targets to improve seizure control. Previous studies have shown that NCX1 can regulate the intracellular Ca²⁺ levels in astrocytes and neurons, which are closely associated with epilepsy. MCC-135 has shown potential as an antiseizure medication due to its ability to downregulate NCX and reduce intracellular calcium overload; however, its role and mechanism in epilepsy remain unclear.

Methods: This study employed single-cell analysis and molecular docking to identify the potential molecular targets of MCC-135 in treating epilepsy. Additionally, we used a KA-induced epileptic mouse model to validate these molecular levels and the therapeutic effects and mechanisms of MCC-135.

Results: Relative to controls, NCX1 expression was significantly upregulated in the hippocampus of KA-induced epileptic mice. Immunofluorescence staining revealed that NCX1 was co-localized with both astrocytes and neurons. MCC-135 treatment significantly prolonged the seizure latency in KA-induced epileptic mice and alleviated hippocampal neuronal damage. Furthermore, MCC-135 effectively reduced NCX1 expression, alleviated intracellular calcium overload, and downregulated glutamate levels in the epileptic mice.

Conclusion: MCC-135 exerts neuroprotective and antiepileptic effects by downregulating NCX1 expression, thereby alleviating calcium overload and reducing glutamate levels in the hippocampus. We are the first to propose the role and mechanism of MCC-135 in epilepsy treatment, providing novel insights into its potential as a therapeutic agent for epilepsy.