Experimental Neurology最新文献

{"title":"miR-15b-5p impairs myelin repair and cognitive recovery after ischemic stroke by targeting the E2F7/CXCL2 axis","authors":"Yizhen Weng ,&nbsp;Jialei Zhou ,&nbsp;Lulu Zhang ,&nbsp;Xinyi He ,&nbsp;Hui Guo ,&nbsp;Quanquan Zhang ,&nbsp;Haiying Li ,&nbsp;Xiang Tang ,&nbsp;Xiang Li Sr","doi":"10.1016/j.expneurol.2025.115589","DOIUrl":"10.1016/j.expneurol.2025.115589","url":null,"abstract":"<div><div>Ischemic stroke often causes demyelination and cognitive impairment. Emerging evidence suggests that microRNAs regulate gene expression and influence myelin repair and cognitive recovery after stroke. Here, transcriptomic analysis and RT-qPCR validation revealed marked upregulation of miR-15b-5p expression in the hippocampal regions of MCAO/R rats. Similarly, elevated serum miR-15b-5p levels were observed in stroke patients and positively correlated with NIHSS scores and infarct volumes. Functional studies involving intracerebroventricular administration of miR-15b-5p agomirs or antagomirs revealed that inhibition of miR-15b-5p markedly enhanced cognitive performance and facilitated myelin repair, as demonstrated by immunofluorescence and transmission electron microscopy. In contrast, overexpression of miR-15b-5p through agomir administration aggravated cognitive impairments and demyelination. Mechanistically, E2F7 was identified as a direct target of miR-15b-5p via dual-luciferase reporter assays. Suppression of E2F7 led to increased expression of the pro-inflammatory chemokine CXCL2, thereby exacerbating neuroinflammation and demyelination. In contrast, inhibition of miR-15b-5p restored E2F7 expression and significantly reduced CXCL2 levels, as confirmed by Western blotting and enzyme-linked immunosorbent assay. Collectively, these findings reveal a novel miR-15b–E2F7–CXCL2 axis that modulates myelin repair and cognitive recovery after ischemic stroke, highlighting miR-15b-5p as a potential therapeutic target.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115589"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meprin β elevates hippocampal soluble Aβ in the APP/V717I mouse model","authors":"Maximilian Keller ,&nbsp;Celine Gallagher ,&nbsp;Liana Marengo ,&nbsp;Kira Bickenbach ,&nbsp;Ulrich Schmitt ,&nbsp;Mohammad Abukhalaf ,&nbsp;Andreas Tholey ,&nbsp;Simon Kreiselmaier ,&nbsp;Christoph Becker-Pauly ,&nbsp;Thomas Mittmann ,&nbsp;Claus U. Pietrzik","doi":"10.1016/j.expneurol.2025.115600","DOIUrl":"10.1016/j.expneurol.2025.115600","url":null,"abstract":"<div><div>The emergence of Alzheimer's disease (AD) pathology has been the focus of multiple hypotheses, with amyloid β (Aβ) playing a central role due to its presence in both familial and sporadic AD. Therefore, a crucial aspect of AD research is understanding the generation of different Aβ species. Aβ peptides result from the proteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases, with BACE1 being the most prominent β-secretase. However, BACE1-overexpressing mouse models exhibit disadvantages, making them limited for AD research. Importantly, N-terminally truncated Aβ species, which constitute up to 70 % of Aβ in AD brains, are not generated by BACE1. In recent years, alternative proteases capable of cleaving APP have been identified, bridging the gap between N-terminally truncated Aβ species and BACE1-derived Aβ. Among these novel players, the metalloprotease meprin β has emerged as a risk factor in AD pathology, generating both N-terminally truncated and full-length Aβ species. Our primary objective was to develop a mouse model that more accurately resembles the pathology of AD beyond BACE1-overexpressing models, while simultaneously confirming APP cleavage of meprin β in the hippocampus and cerebral cortex. Overexpression of meprin β led to a marked increase in soluble Aβ levels, particularly in the hippocampus, indicating a higher vulnerability or elevated meprin β activity in this region compared to the cerebral cortex. Notably, this biochemical change occurred without any observable behavioral deficits, suggesting a region-specific role of meprin β in AD pathology that may extend beyond immediate functional impairment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115600"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new microinfarcts model produces widespread bilateral infarcts and persistent cognitive deficits in middle-aged mice","authors":"Zhongwu Liu ,&nbsp;Mikkala Mccann ,&nbsp;Brianna Powell ,&nbsp;Julie Landschoot-Ward ,&nbsp;Zheng Gang Zhang ,&nbsp;Michael Chopp","doi":"10.1016/j.expneurol.2025.115598","DOIUrl":"10.1016/j.expneurol.2025.115598","url":null,"abstract":"<div><h3>Background</h3><div>Multi-infarct dementia (MID), a severe form of vascular cognitive impairment, results from cumulative impact of multiple cerebral microinfarcts (MMIs). Current preclinical models primarily rely on unilateral induction of MMIs, which fails to reproduce bilateral lesion distribution and persistent cognitive decline characteristic of human disease.</div></div><div><h3>Objective</h3><div>To develop and characterize a modified bilateral MMI model that more accurately reflects the clinical and pathological features of MID.</div></div><div><h3>Methods</h3><div>Twelve-month-old male C57BL/6J mice underwent either unilateral or bilateral MMI induction by microsphere embolization via the internal carotid artery. Bilateral induction was achieved by transiently occluding the contralateral common carotid artery during microsphere infusion. Behavioral assessments using novel object recognition (NOR) and elevated plus maze (EPM) were conducted on days 7, 14, and 28 post-surgery. Histological Hematoxylin and Eosin staining and immunohistochemical analyses using antibodies against Iba1 and GFAP were performed to evaluate lesion distribution and neuroinflammation.</div></div><div><h3>Results</h3><div>The modified bilateral procedure successfully induced widespread infarcts across both hemispheres. Bilateral MMI mice exhibited significantly greater and persistent cognitive impairment, demonstrated by a reduced NOR discrimination index and decreased open-arm exploration in the EPM persisting through day 28, than did unilateral MMI mice. Histological analysis confirmed bilateral microinfarcts and significant increase in Iba1- and GFAP-positive staining, indicating robust and sustained bilateral neuroinflammation.</div></div><div><h3>Conclusion</h3><div>This modified bilateral MMI procedure reproduces key pathological and functional features of human MID, overcoming the limitations of traditional unilateral models. The new model provides a clinically relevant platform for investigating mechanisms underlying vascular cognitive impairment and evaluating potential disease-modifying therapies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115598"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimizing functional recovery after acute ischemic stroke through intensity and frequency of rehabilitation: The critical role of HIF-1α/PLD2/mTOR signaling mechanisms","authors":"Qingzhu Wang ,&nbsp;Yanna Tong ,&nbsp;Yuchuan Ding ,&nbsp;Alexander Weiss ,&nbsp;Aminah I. Fayyaz ,&nbsp;Xiaokun Geng","doi":"10.1016/j.expneurol.2025.115568","DOIUrl":"10.1016/j.expneurol.2025.115568","url":null,"abstract":"<div><h3>Objectives</h3><div>This study aims to identify the most optimal rehabilitation strategy for acute ischemic stroke recovery by examining the effects of different mobilization intensities and frequencies, and investigating the underlying mechanisms involving the HIF-1α/PLD2/mTOR signaling pathway.</div></div><div><h3>Methods</h3><div>A total of 152 adult male Sprague-Dawley rats were subjected to 2-h middle cerebral artery occlusion (MCAO) and divided into five groups to compare high-intensity exercise versus low-intensity exercise with interval (5 cycles of 5-min exercise and 5-min rest) versus continuous (30-min continuous exercise) sessions. The groups were as followed stroke-only, stroke with high-intensity-continuous (HC) exercise, stroke with high-intensity-interval (HI) exercise, stroke with low-intensity-continuous (LC) exercise, and stroke with low-intensity-interval (LI) exercise. Brain damage was assessed by measuring infarct volume, neurological deficits, and neuronal death. The long-term functional outcomes were evaluated using the adhesive tape touch, grid walk, Rota-rod, beam balance, and forelimb placing at days 7, 14, and 28. Neuroplasticity was measured by synaptogenesis [synaptophysin (SYN), post-synaptic density protein-95 (PSD-95)], and myelination [myelin-associated glycoprotein (MAG), myelin basic protein (MBP)]. The key role of regulatory molecules- hypoxia inducible factor 1α (HIF-1α), phospholipase D2 (PLD2), and the mechanistic target of rapamycin (mTOR) pathway- was also assessed.</div></div><div><h3>Results</h3><div>All exercise modalities significantly reduced infarct volumes, improved neurological deficits, and enhanced functional recovery (<em>P</em> <em>&lt;</em> 0.05). In the low-intensity exercise groups, the LC rats showed a greater reduction in infarct volume and increased functional outcomes compared to the LI group (<em>P</em> <em>&lt;</em> 0.05). Among the high-intensity exercise groups, long-term functional outcomes were significantly improved in the HI group compared to HC (<em>P</em> <em>&lt;</em> 0.05). Both HI and LC significantly outperformed their counterparts in protecting hippocampal CA1 neurons, promoting synaptogenesis and myelination, and enhancing neuroplasticity signaling (<em>P</em> <em>&lt;</em> 0.05). However, no major differences were observed between HI and LC in these outcomes. Activation of the HIF-1α/PLD2/mTOR pathway was identified as a key mechanism underlying the neuroplastic effects of rehabilitation, with HIF-1α inhibition further confirming its critical role.</div></div><div><h3>Conclusion</h3><div>Exercise rehabilitation, particularly the LC and HI protocols, significantly improves motor function post-stroke, likely through the HIF-1α/PLD2/mTOR pathway. These findings suggest that LC and HI exercise are promising clinical rehabilitation strategies for optimizing stroke recovery, warranting further clinical investigation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115568"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1 Box A gene therapy reverses cognitive and neuropathological features in AlCl₃/D-galactose rat model of Alzheimer's disease","authors":"Suangsuda Supasai ,&nbsp;Pakawat Suntaratti ,&nbsp;Mingkwan Odton ,&nbsp;Tasneem Longji ,&nbsp;Thararat Karananan ,&nbsp;Sakawdaurn Yasom ,&nbsp;Sumate Ampawong ,&nbsp;Yanin Limpanont ,&nbsp;Apiwat Mutirangura","doi":"10.1016/j.expneurol.2025.115583","DOIUrl":"10.1016/j.expneurol.2025.115583","url":null,"abstract":"<div><div>Alzheimer's disease (AD), the leading cause of dementia, is pathologically defined by the accumulation of amyloid-β and tau pathology, resulting in progressive cognitive decline. Our previous work demonstrated that high mobility group box 1 (HMGB1) Box A plasmids alleviated cellular senescence and restored cognitive performance in aged rat models, supporting their therapeutic potential for neurodegenerative disorders such as AD. In this study, we investigated the efficacy of HMGB1 Box A gene therapy in an AD-like rat model chronically induced by AlCl₃ and D-galactose. Following the onset of AD pathology, Box A plasmids were administered weekly at varying doses over eight weeks. Box A treatment significantly improved behavioral outcomes, including responsiveness, locomotor activity, and learning and memory performance. At the neuropathological level, Box A reduced hippocampal Aβ accumulation and tau pathology, restored neuronal density, and attenuated synaptic degeneration. Moreover, it suppressed hippocampal microgliosis, astrogliosis, and the expression of proinflammatory mediators. Box A also diminished markers of cellular senescence in the hippocampus. These findings demonstrate that HMGB1 Box A gene therapy confers multi-level neuroprotective effects in AD, from molecular and cellular restoration to behavioral recovery. This strategy holds strong promise as a disease-modifying treatment for AD, contributing to improved well-being by advancing therapeutic innovation to promote healthy aging and combat age-related neurodegenerative diseases.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115583"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tracking remyelination in a model of multiple sclerosis: Visual evoked potentials reveal therapeutic effect from brain stimulation and exercise","authors":"Elena Rossi ,&nbsp;Silvia Marenna ,&nbsp;Valerio Castoldi ,&nbsp;Elena Criscuolo ,&nbsp;Benedetta Giuliani ,&nbsp;Chiara Malacrida ,&nbsp;Nicola Clementi ,&nbsp;Giancarlo Comi ,&nbsp;Letizia Leocani","doi":"10.1016/j.expneurol.2025.115565","DOIUrl":"10.1016/j.expneurol.2025.115565","url":null,"abstract":"<div><div>Visual evoked potentials (VEPs) represent an accurate, fast, and cost-effective diagnostic tool to evaluate visual function in multiple sclerosis (MS), and its use in preclinical research can support longitudinal monitoring of treatments effects with implications for translational purposes. Anodal transcranial direct current stimulation (tDCS) and physical exercise (PE) are known to exert neuromodulatory effects on the central nervous system, increasing brain activity, promoting plasticity and remyelination. To improve our understanding of the effects of tDCS and PE on demyelination/remyelination processes and refine its therapeutic use in MS, VEPs were employed to monitor the mouse visual pathway during cuprizone (CPZ) demyelination including before and after therapeutic interventions. In CPZ-fed mice, VEP latency delays were associated with MBP loss in the dorsolateral geniculate nucleus (dLGN) confirming VEP as a biomarker of demyelination in the subcortical visual pathway. Combination of anodal tDCS and PE showed a strong beneficial effect on VEP latency during CPZ demyelination. Both VEP latency and behavioural motor function improvements were stronger after combined protocols, highlighting the potential of this multimodal approach in demyelinating conditions. Differential and synergistic contribution by anodal tDCS and PE was associated with reduced microglia/macrophage levels whilst effects on myelin by the first, and reduced cell death and BDNF protein were driven by the second. VEPs efficiency to detect modulation of visual function by brain stimulation and physical activity, strongly correlated with myelin changes in the visual pathway, providing a potent platform for the translatability of preclinical findings to the clinic.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115565"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145586532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular insights into hydrocephalus: The diverse roles and intricate crosstalk of multiple cell types","authors":"Xu Li ,&nbsp;Yuxiang Zhou ,&nbsp;Yang Han ,&nbsp;Xun Chen ,&nbsp;Qian Ouyang","doi":"10.1016/j.expneurol.2025.115596","DOIUrl":"10.1016/j.expneurol.2025.115596","url":null,"abstract":"<div><div>Hydrocephalus is characterized by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain's ventricular system, which can lead to ventricular dilation. This condition affects individuals across all age groups but is particularly prevalent in infants and the elderly. The etiology of hydrocephalus is multifactorial, involving excessive CSF secretion, obstruction of CSF pathways, and impairment of CSF reabsorption. Recent evidence supports the CSF permeation theory, which emphasizes the exchange of CSF with blood and interstitial fluid throughout the brain, mediated by perivascular spaces, astrocytes, and brain parenchyma. This review focuses on the role and interactions of various cell types in CSF circulation and the development of hydrocephalus, including choroid plexus cells, choroid plexus macrophages, vascular endothelial cells, neural progenitor cells, perivascular macrophages, mast cells, astrocytes, ependymal cells, and meningeal lymphatic endothelial cells(mLECs). We discuss the mechanisms by which these cells contribute to hydrocephalus, such as the disruption of blood-CSF-barrier integrity, inflammation, and alterations in CSF dynamics. Additionally, we explore potential therapeutic strategies targeting these cellular interactions, such as the inhibition of chemokine signaling and the modulation of complement pathways. Understanding the complex interplay between different cell types is crucial for developing novel treatments for hydrocephalus. This review provides a comprehensive overview of the current knowledge regarding cellular contributions to hydrocephalus and highlights areas for future research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115596"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145755662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholinergic modulation of hippocampal CA1 pyramidal cell excitability in ArxGCG+7 mice","authors":"Christopher M. Johnson ,&nbsp;Joseph Dong ,&nbsp;Peace Senkungu ,&nbsp;Jahnvi Chandar ,&nbsp;Natalia Ochoa-Sepulveda ,&nbsp;Almedia J. Myers ,&nbsp;Eric D. Marsh","doi":"10.1016/j.expneurol.2025.115591","DOIUrl":"10.1016/j.expneurol.2025.115591","url":null,"abstract":"<div><div>Developmental and Epileptic Encephalopathies (DEE) are rare neurodevelopmental disorders defined by seizures, developmental delays, and abnormal EEG patterns. Infantile Spasms Syndrome (ISS), the most common DEE, was one of the first linked to single-gene variants, including polyalanine expansions in the <em>Aristaless Related Homeobox</em> (<em>ARX</em>) gene. The Arx^GCG+7 mouse, which models the human mutation, exhibits behavioral phenotypes, epileptiform hippocampal activity, and reduced cholinergic input to the hippocampus. The role of the disrupted cholinergic signaling has not been explored in this model and may be contributing to hippocampal dysfunction and DEE pathogenesis. Hence, we investigated the impact of the <em>ARX</em> GCG expansion on the septo-hippocampal network by first reproducing the changes in Choline acetyltransferase (ChAT) protein levels in the medial septum (MS) and diagonal band of Broca (DBB). Next, we performed ex vivo patch-clamp recordings in CA1 pyramidal neurons and measured responses to cholinergic agonists. Finally, we assessed acetylcholine receptor expression by western blot across the hippocampus to assess for homeostatic changes in receptors. Our data demonstrated a ∼ 60 % reduction in ChAT expression in the MS and DBB of Arx^GCG+7 mice. The Arx^GCG+7 CA1 pyramidal neurons exhibited increased firing activity and reduced sag potential. Despite reduced ChAT, carbachol- and pilocarpine-induced firing responses were preserved, while nicotinic receptor-mediated excitation was abolished. Carbachol-induced depolarization block threshold was elevated in mutants. Molecular analysis revealed increased muscarinic receptor 1 expression and decreased β4 nicotinic receptor expression in CA1.Together, these findings demonstrate histological, electrophysiological, and molecular alterations in the septo-hippocampal network of Arx^GCG+7 mice. Together, they suggest impaired cholinergic signaling contributes to ISS pathogenesis and highlight the cholinergic system as a potential therapeutic target.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115591"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Noninvasive deep brain stimulation using theta-burst transcranial magnetic-acoustic coupling to modulate cortical rhythms in Parkinsonian mice","authors":"Ruixu Liu ,&nbsp;Ruru Wang ,&nbsp;Xiaoqing Zhou ,&nbsp;Fangxuan Chu ,&nbsp;Yuheng Wang ,&nbsp;Kai Zhu ,&nbsp;Shunqi Zhang ,&nbsp;Ren Ma ,&nbsp;Zhipeng Liu","doi":"10.1016/j.expneurol.2025.115592","DOIUrl":"10.1016/j.expneurol.2025.115592","url":null,"abstract":"<div><div>Modulating the subthalamic nucleus (STN) through neural circuits can suppress abnormal discharge rhythms in the primary motor cortex (M1) in Parkinson's disease (PD), thereby enhancing motor function. However, a clinically viable noninvasive deep brain stimulation method for PD has yet to be realized. We developed a noninvasive transcranial magnetic-acoustic coupling stimulation (TMAS) system, employing a theta burst stimulation (TBS) mode, to examine its effects of simulated electrical parameters on cortical rhythms in PD. The theta burst-TMAS (TBTMAS) system was established, and its physical performance parameters were evaluated. The STN of MPTP-induced Parkinsonian mice was targeted using both continuous TBTMAS (cTBTMAS) and intermittent TBTMAS (iTBTMAS) modes. Local field potentials (LFPs) in the M1 were recorded before and after stimulation to assess pathological biomarkers associated with PD. Results showed that both TBTMAS protocols significantly suppressed abnormal beta oscillations and reduced beta power spectral density (PSD) in the M1 of PD mice. In addition, both modes decreased the beta–ripple phase–amplitude coupling (PAC) index and disrupted PAC locking. Notably, the iTBTMAS mode exhibited a more substantial inhibitory effect on beta PSD and enhanced the downmodulation and decoupling of beta–high gamma PAC phase-locking. These findings suggest that TBTMAS can effectively regulate pathological oscillatory activity in the M1 of PD models, offering a promising non-invasive approach for deep brain stimulation therapy.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115592"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression","authors":"Larissa Robinson-Cooper ,&nbsp;Stephanie Davidson ,&nbsp;Rami Koutoubi ,&nbsp;Kangni Zhang ,&nbsp;Hannah Park ,&nbsp;Melissa Barker-Haliski","doi":"10.1016/j.expneurol.2025.115586","DOIUrl":"10.1016/j.expneurol.2025.115586","url":null,"abstract":"<div><div>Presenilin 2 (PSEN2) variants increase risk of Alzheimer's disease (AD) and unprovoked seizures. Yet, age-related PSEN2 contributions to seizure susceptibility are understudied. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptor (KAR) availability. Kainic acid (KA) is a KAR agonist that evokes severe seizures in mice. We hypothesized that PSEN2 knockout (KO) mice would show reduced latency to KA-induced seizures, increased seizure burden, worsened 7-day survival, and altered hippocampal KAR expression compared to wild-type (WT) controls. Using repeated low-dose systemic KA administration to 3–4- and 12–15-month-old PSEN2 KO versus WT mice, we quantified acute seizure latency and neuropathology. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes 7 days after seizures or sham to assess the impact of PSEN2 loss and seizures on hippocampal KARs. Young PSEN2 KO mice were more seizure-prone than WT mice, while genotype did not change latency to first seizure in aged mice. Aged females seized faster than young females and experienced greater mortality, unlike males. There was no difference in KAR subunit expression between young mouse genotypes and regardless of seizure history. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 after seizures, however, astrocytic GluK2 upregulation only occurred in WT mice. GluK5 expression was significantly reduced in aged seizure-naïve PSEN2 KO versus WT mice, while total GluK2 expression did not differ. Seizure-induced astrocytic GluK5 expression only occurred in WT mice in CA3, while astrocytic GluK2 expression occurred in both. Thus, PSEN2 loss may impair age-related hippocampal KAR expression, implicating KARs as understudied contributors to AD-related seizures.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"397 ","pages":"Article 115586"},"PeriodicalIF":4.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}