Neuroscience
Abstract
Deficits in the mitochondrial energy-generating machinery cause mitochondrial disease (MD), a group of untreatable and usually fatal disorders. Among many severe symptoms, refractory epileptic events are a common neurological presentation of MD. However, the neuronal substrates and circuits for MD-induced epilepsy remain unclear. Here, using mouse models of Leigh Syndrome, a severe form of MD associated to epilepsy, that lack mitochondrial complex I subunit NDUFS4 in a constitutive or conditional manner, we demonstrate that mitochondrial dysfunction leads to a reduction in the number of GABAergic neurons in the rostral external globus pallidus (GPe), and identify a specific affectation of pallidal Lhx6-expressing inhibitory neurons, contributing to altered GPe excitability. Our findings further reveal that viral vector-mediated Ndufs4 re-expression in the GPe effectively prevents seizures and improves the survival in the models. Additionally, we highlight the subthalamic nucleus (STN) as a critical structure in the neural circuit involved in mitochondrial epilepsy, as its inhibition effectively reduces epileptic events. Thus, we have identified a role for pallido-subthalamic projections in the development of epilepsy in the context of mitochondrial dysfunction. Our results suggest STN inhibition as a potential therapeutic intervention for refractory epilepsy in patients with MD providing promising leads in the quest to identify effective treatments.
Authors
Laura Sánchez-Benito, Melania González-Torres, Irene Fernández-González, Laura Cutando, María Royo, Joan Compte, Miquel Vila, Sandra Jurado, Elisenda Sanz, Albert Quintana
Abstract
BACKGROUND Inter- and intraindividual fluctuations in pain intensity pose a major challenge to treatment efficacy, with a majority of people perceiving their pain relief as inadequate. Recent preclinical studies have identified circadian rhythmicity as a potential contributor to these fluctuations and a therapeutic target.METHODS We therefore sought to determine the impact of circadian rhythms in people with chronic low back pain (CLBP) through a detailed characterization, including questionnaires to evaluate biopsychosocial characteristics, ecological momentary assessment (7 day e-diaries at 8:00/14:00/20:00) to observe pain fluctuations, and intraday blood transcriptomics (at 8:00/20:00) to identify genes/pathways of interest.RESULTS While most individuals displayed constant or variable/mixed pain phenotypes, a distinct subset had daily fluctuations of increasing pain scores (>30% change in intensity over 12 hours in ≥4/7 days). This population had no opioid users, better biopsychosocial profiles, and differentially expressed transcripts relative to other pain phenotypes. The circadian-governed neutrophil degranulation pathway was particularly enriched among arrhythmic individuals; the link between neutrophil degranulation and opioid use was further confirmed in a separate CLBP cohort.CONCLUSION Our findings identified pain rhythmicity and the circadian expression of neutrophil degranulation pathways as indicators of CLBP outcomes, which may help provide a personalized approach to phenotyping biopsychosocial characteristics and medication use. This highlights the need to better understand the impact of circadian rhythmicity across chronic pain conditions.FUNDING This work was funded by grants from the Canadian Institutes of Health Research (CIHR; grant PJT-190170, to NG and MGP) and the CIHR-Strategy for Patient-Oriented Research Chronic Pain Network (grant SCA-145102, to NG, QD, LD, MGP, and MC). DT was funded by a MS Canada endMS Doctoral Research Award, AMZ by an Ontario Graduate Scholarship, HGMG by a CIHR Doctoral Research Award, MGP by a Junior 2 Research Scholarship from the Fonds de recherche du Québec – Santé, and LD by a Canadian Excellence Research Chairs and Pfizer Canada Professorship in Pain Research.
Authors
Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou
Abstract
Whether amyloid-β (Aβ) peptides are synaptogenic or synaptotoxic remains a pivotal open question in Alzheimer’s disease research. Here, we chronically treated human neurons with precisely controlled concentrations of chemically defined synthetic Aβ40, Aβ42, and Aβ42arctic peptides that exhibit distinct aggregation propensities. Remarkably, chronic exposure of human neurons to free Aβ40 at higher concentrations or to free Aβ42 at lower concentrations potently promoted synapse formation. In contrast, aggregated Aβ42 or Aβ42arctic at higher concentrations were neurotoxic and synaptotoxic. The synaptotoxic effects of Aβ peptides manifested as an initial contraction of the synaptic vesicle cluster followed by synapse loss. Aβ40 and Aβ42 peptides with scrambled or inverted sequences were inactive. Thus, our experiments reveal that Aβ peptides exhibit an aggregation-dependent functional dichotomy that renders them either synaptogenic or synaptotoxic, thereby providing insight into how Aβ peptides straddle a thin line between physiological synapse organization and pathological synapse disruption. Among others, our data suggest that Alzheimer’s disease therapies might aim to shift the balance of Aβ peptides from the aggregated to the free state instead of suppressing all Aβ peptides.
Authors
Alberto Siddu, Silvia Natale, Connie H. Wong, Hamidreza Shaye, Thomas C. Südhof
Abstract
The Integrator complex plays essential roles in RNA polymerase II transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional knockout (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice displayed a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNA polymerase II dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere over-proliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.
Authors
Xiaoxia Peng, Xiangbin Jia, Hanying Wang, Jingjing Chen, Xiaolei Zhang, Senwei Tan, Xinyu Duan, Can Qiu, Mengyuan Hu, Haiyan Hou, Ilaria Parenti, Alma Kuechler, Frank J. Kaiser, Alicia Renck, Raymond Caylor, Cindy Skinner, Joseph Peeden, Benjamin Cogne, Bertrand Isidor, Sandra Mercier, Gael Nicolas, Anne-Marie Guerrot, Flavio Faletra, Luciana Musante, Lior Cohen, Gaber Bergant, Goran Čuturilo, Borut Peterlin, Andrea Seeley, Kristine Bachman, Julian A. Martinez-Agosto, Conny van Ravenswaaij-Arts, Dennis Bos, Katherine H. Kim, Tobias Bartolomaeus, Zelia Schmederer, Rami Abou Jamra, Erfan Aref-Eshghi, Wenjing Zhao, Yongyi Zou, Zhengmao Hu, Qian Pan, Faxiang Li, Guodong Chen, Jiada Li, Zhangxue Hu, Kun Xia, Jieqiong Tan, Hui Guo
Abstract
Authors
Steven Q. Le, Alexander Sorensen, Soila Sukupolvi, Gianna Jewhurst, Grant L. Austin, Balraj Doray, Jonathan D. Cooper, Patricia I. Dickson
Abstract
Degeneration of the neuromuscular system is a characteristic feature of spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene targeted mouse model of SBMA, AR113Q mice, we demonstrate age-dependent degeneration of the neuromuscular system that initially manifests with muscle weakness and atrophy and progresses to include denervation of neuromuscular junctions and lower motor neuron soma atrophy. Using this model, we tested the hypothesis that therapeutic intervention targeting skeletal muscle during this period of disease progression arrests degeneration of the neuromuscular system. To accomplish this, AR-targeted antisense oligonucleotides were administered subcutaneously to symptomatic AR113Q mice to reduce expression of polyQ AR in peripheral tissues but not in the spinal cord. This intervention rescued muscle atrophy, neuromuscular junction innervation, lower motor neuron soma size, and survival in aged AR113Q mice. Single-nucleus RNA sequencing revealed age-dependent transcriptional changes in the AR113Q spinal cord during disease progression which were mitigated by peripheral AR gene silencing. Our findings underscore the intricate interplay between peripheral tissues and the central nervous system in SBMA and emphasize the therapeutic effectiveness of peripheral gene knockdown in symptomatic disease.
Authors
Changwoo Lee, Zhigang Yu, Curtis J. Kuo, Leon Tejwani, Rosalie M. Grijalva, Eunwoo Bae, Hien T. Zhao, Janghoo Lim, Andrew P. Lieberman
Abstract
The incretin receptor agonists semaglutide and tirzepatide have transformed the medical management of obesity. The neural mechanisms by which incretin analogs regulate appetite remain incompletely understood, and dissecting this process is critical for the development of next-generation anti-obesity drugs that are more targeted and tolerable. Moreover, the physiologic functions of incretins in appetite regulation and gut-brain communication have remained elusive. Using in vivo fiber photometry, we discovered distinct pharmacologic and physiologic roles for the incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). We showed that GIP, but not GLP-1, was required for normal nutrient-mediated inhibition of hunger-promoting AgRP neurons. By contrast, both GIP and GLP-1 analogs at pharmacologic doses were sufficient to inhibit AgRP neurons. The magnitude of neural inhibition was proportional to the effect of each incretin on food intake, and dual GIP and GLP-1 receptor agonism more potently inhibited AgRP neurons and suppressed food intake than either agonist alone. Our results have revealed a role for endogenous GIP in gut-brain appetite regulation and indicate that incretin analogs act in part via AgRP neurons to mediate their anorectic effects.
Authors
Hayley E. McMorrow, Andrew B. Cohen, Carolyn M. Lorch, Nikolas W. Hayes, Stefan W. Fleps, Joshua A. Frydman, Jessica L. Xia, Ricardo J. Samms, Lisa R. Beutler
Abstract
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase in the brain. Mutations in PPP2R1A, encoding the scaffolding subunit, are linked to intellectual disability, although the underlying mechanisms remain unclear. This study examined mice with heterozygous deletion of Ppp2r1a in forebrain excitatory neurons (NEX-het-conditional knockout, NEX-het-cKO). These mice exhibited impaired spatial learning and memory, resembling Ppp2r1a-associated intellectual disability. Ppp2r1a haploinsufficiency also led to increased excitatory synaptic strength and reduced inhibitory synapse numbers on pyramidal neurons. The increased excitatory synaptic transmission was attributed to increased presynaptic release probability (Pr), likely due to reduced levels of 2-arachidonoyl glycerol (2-AG). This reduction in 2-AG was associated with increased transcription of monoacylglycerol lipase (MAGL), driven by destabilization of enhancer of zeste homolog 2 (EZH2) in NEX-het-cKO mice. Importantly, the MAGL inhibitor JZL184 effectively restored both synaptic and learning deficits. Our findings uncover an unexpected role of PPP2R1A in regulating endocannabinoid signaling, providing fresh molecular and synaptic insights into the mechanisms underlying intellectual disability.
Authors
Yirong Wang, Weicheng Duan, Hua Li, Zhiwei Tang, Ruyi Cai, Shangxuan Cai, Guanghao Deng, Liangpei Chen, Hongyan Luo, Liping Chen, Yulong Li, Jian-Zhi Wang, Bo Xiong, Man Jiang
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus caused by metabolic toxicity to peripheral axons. We aimed to gain deep mechanistic insight into the disease using transcriptomics on tibial and sural nerves recovered from lower leg amputations in a mostly diabetic population and control sural nerves from cross facial nerve graft surgery. First, comparing DPN versus control sural nerves revealed inflammatory activation and sensory changes in DPN. Second, when comparing mixed sensory and motor tibial and purely sensory sural nerves, we identified key pathway differences in affected DPN nerves, with distinct immunological features observed in sural nerves. Third, spatial transcriptomics of sural nerves revealed shifts in immune cell types associated with axonal loss progression. We also found clear evidence of neuronal transcript changes, like PRPH, in nerves with axonal loss, suggesting perturbed RNA transport into distal sensory axons. This motivated further investigation into neuronal mRNA localization in peripheral nerve axons, generating evidence of robust localization of mRNAs such as SCN9A and TRPV1 in human sensory axons. Our work provides insight into altered cellular and transcriptomic profiles in human nerves in DPN and highlights sensory axon mRNA transport as a potential contributor to nerve degeneration.
Authors
Diana Tavares-Ferreira, Breanna Q. Shen, Juliet M. Mwirigi, Stephanie Shiers, Ishwarya Sankaranarayanan, Akshitha Sreerangapuri, Miriam B. Kotamarti, Nikhil N. Inturi, Khadijah Mazhar, Eroboghene E. Ubogu, Geneva L. Thomas, Trapper Lalli, Shai M. Rozen, Dane K. Wukich, Theodore J. Price
Abstract
Anxiety disorders pose a substantial threat to global mental health, with chronic stress identified as a major etiologic factor. Over the past few decades, extensive studies have revealed that chronic stress induces anxiety states through a distributed neuronal network of interconnected brain structures. However, the precise circuit mechanisms underlying the transition from chronic stress to anxiety remain incompletely understood. Employing the chronic social defeat stress (CSDS) paradigm in mice, we uncovered a critical role of the parasubthalamic nucleus (PSTh) in both the induction and expression of anxiety-like behavior. The anxiogenic effect was mediated by an excitatory trisynaptic circuitry involving the lateral parabrachial nucleus (LPB), PSTh, and bed nucleus of the stria terminalis (BNST). Furthermore, CSDS downregulated Kv4.3 channels in glutamatergic neurons of the PSTh. Reexpression of these channels dampened neuronal overexcitability and alleviated anxiety-like behavior in stressed animals. In parallel with the well-known anxiety network centered on the amygdala, here we identify a noncanonical LPB-PSTh-BNST pathway in the transformation of stress into anxiety. These findings suggest that the PSTh may serve as a potential therapeutic target for anxiety-related disorders.
Authors
Na Liu, Jun Wang, Huan Wang, Bin Gao, Zheng Lin, Tian-Le Xu, Shumin Duan, Han Xu
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)