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Neurosciences

  • 551 Articles
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Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia
Longlong Tu, … , Yanlin He, Yong Xu
Longlong Tu, … , Yanlin He, Yong Xu
Published June 1, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI163391.
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Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia

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Abstract

Although glucose is the basic fuel essential to maintain the viability and functions of all cells, some neurons, namely glucose-inhibited (GI) neurons, paradoxically increase their firing activities when glucose falls and are inhibited by high glucose. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here we showed that currents mediated by anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of non-Ano4 neurons in the VMH suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Authors

Longlong Tu, Jonathan C. Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas Anthony Scarcelli, Kristine Marie Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

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Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome
Saja Fadila, … , Eric J. Kremer, Moran Rubinstein
Saja Fadila, … , Eric J. Kremer, Moran Rubinstein
Published May 16, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI159316.
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Viral vector-mediated expression of NaV1.1, after seizure onset, reduces epilepsy in mice with Dravet syndrome

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Abstract

Dravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is typically caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1, a 250-kDa voltage-gated sodium channel. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A open reading frame into the brain improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus and/or the thalamus of DS mice increased survival, reduced the occurrence of epileptic spikes, provided protection from thermally-induced seizures, corrected background electrocorticography activity and behavioral deficits, and restored hippocampal inhibition. Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.

Authors

Saja Fadila, Bertrand Beucher, Iria González Dopeso-Reyes, Anat Mavashov, Marina Brusel, Karen Anderson, Caroline Ismeurt, Ethan M. Goldberg, Ana Ricobaraza, Ruben Hernandez-Alcoceba, Eric J. Kremer, Moran Rubinstein

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Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons
Jie Sun, … , Li Zhang, Rong-Rong He
Jie Sun, … , Li Zhang, Rong-Rong He
Published May 15, 2023
Citation Information: J Clin Invest. 2023;133(10):e165228. https://doi.org/10.1172/JCI165228.
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Midbrain dopamine oxidation links ubiquitination of glutathione peroxidase 4 to ferroptosis of dopaminergic neurons

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the gradual loss of midbrain dopaminergic neurons in association with aggregation of α-synuclein. Oxidative damage has been widely implicated in this disease, though the mechanisms involved remain elusive. Here, we demonstrated that preferential accumulation of peroxidized phospholipids and loss of the antioxidant enzyme glutathione peroxidase 4 (GPX4) were responsible for vulnerability of midbrain dopaminergic neurons and progressive motor dysfunctions in a mouse model of PD. We also established a mechanism wherein iron-induced dopamine oxidation modified GPX4, thereby rendering it amenable to degradation via the ubiquitin-proteasome pathway. In conclusion, this study unraveled what we believe to be a novel pathway for dopaminergic neuron degeneration during PD pathogenesis, driven by dopamine-induced loss of antioxidant GPX4 activity.

Authors

Jie Sun, Xiao-Min Lin, Dan-Hua Lu, Meng Wang, Kun Li, Sheng-Rong Li, Zheng-Qiu Li, Cheng-Jun Zhu, Zhi-Min Zhang, Chang-Yu Yan, Ming-Hai Pan, Hai-Biao Gong, Jing-Cheng Feng, Yun-Feng Cao, Feng Huang, Wan-Yang Sun, Hiroshi Kurihara, Yi-Fang Li, Wen-Jun Duan, Gen-Long Jiao, Li Zhang, Rong-Rong He

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Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination
Vetrivel Sengottuvel, … , Federico Torta, David L. Silver
Vetrivel Sengottuvel, … , Federico Torta, David L. Silver
Published April 27, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI164118.
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Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination

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Abstract

Patients with Autosomal Recessive Microcephaly 15 caused by deficiency in the sodium-dependent lysophosphatidylcholine (LPC) transporter Major Facilitator Superfamily Domain containing 2a (Mfsd2a) present with both microcephaly and hypomyelination, suggesting an important role of LPC uptake by oligodendrocytes in the process of myelination. Here, we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPC) and is critical for oligodendrocyte development. Single cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a KO mice (2aOKO) underwent precocious differentiation into immature oligodendrocytes (iOLs) and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, consistent with microcephaly being consequential to absence of LPC uptake at the blood-brain barrier and not from deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased phospholipids containing omega-3 fatty acids with an opposite increase in unsaturated fatty acids, that latter being products of de novo synthesis governed by Srebp-1. RNA sequencing indicated activation of the Srebp-1 pathway and defective expression of regulators of oligodendrocyte development. Taken together, these findings indicate that the transport of LPCs by Mfsd2a in OPCs is important for maintaining OPC cell state to regulate postnatal brain myelination.

Authors

Vetrivel Sengottuvel, Monalisa Hota, Jeongah Oh, Dwight L. Galam, Bernice H. Wong, Markus R. Wenk, Sujoy Ghosh, Federico Torta, David L. Silver

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Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model
Keigo Takahashi, … , Michael Wong, Jonathan D. Cooper
Keigo Takahashi, … , Michael Wong, Jonathan D. Cooper
Published April 27, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI165908.
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Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

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Abstract

Although a disease-modifying therapy for CLN2 disease now exists, a poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients, but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities including spontaneous seizures, providing a robust and quantifiable disease-relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord, and differs markedly from the staging seen in mouse models of other forms of NCL. Neonatal administration of adeno-associated virus 9 (AAV9)-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the lifespan of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging pre-clinical efficacy of therapeutic interventions for CLN2 disease.

Authors

Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, Nicholas R. Rensing, Hemanth R. Nelvagal, Joshua T. Dearborn, Olivier Danos, Nicholas Buss, Mark S. Sands, Michael Wong, Jonathan D. Cooper

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Postoperative risk of IDH mutant glioma-associated seizures and their potential management with IDH mutant inhibitors
Michael Drumm, … , Geoffrey T. Swanson, Craig Horbinski
Michael Drumm, … , Geoffrey T. Swanson, Craig Horbinski
Published April 27, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI168035.
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Postoperative risk of IDH mutant glioma-associated seizures and their potential management with IDH mutant inhibitors

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Abstract

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contribute to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures are often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, D-2-hydroxyglutarate, rapidly synchronizes neuronal spike firing in a seizure-like manner, but only when nonneoplastic glial cells are present. In vitro and in vivo models can recapitulate IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibit seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Authors

Michael Drumm, Wenxia Wang, Thomas K. Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y. Cotton, Brynna T. Webb, Kayla T. Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V. Lukas, Joanna J. Phillips, Esraa Mohamed, John D. Finan, Lucas Santana-Santos, Amy B. Heimberger, Colin K. Franz, Jonathan E. Kurz, Jessica W. Templer, Geoffrey T. Swanson, Craig Horbinski

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Silencing miR-21-5p in sensory neurons reverses neuropathic allodynia via activation of TGFB-related pathway in macrophages
Lynda Zeboudj, … , David Chambers, Marzia Malcangio
Lynda Zeboudj, … , David Chambers, Marzia Malcangio
Published April 18, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI164472.
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Silencing miR-21-5p in sensory neurons reverses neuropathic allodynia via activation of TGFB-related pathway in macrophages

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Abstract

Neuropathic pain remains poorly managed by current therapies highlighting the need to improve our knowledge of chronic pain mechanisms. In neuropathic pain models, dorsal root ganglia (DRG) nociceptive neurons transfer miR-21 packaged in extracellular vesicles to macrophages that promote pro-inflammatory phenotype and contribute to allodynia. Here we show that miR-21 conditional deletion in DRG neurons was coupled with lack of up-regulation of CCL2 chemokine after nerve injury and reduced accumulation of CCR2-expressing macrophages, which showed TGFB-related pathway activation and acquired M2-like anti-nociceptive phenotype. Indeed, neuropathic allodynia was attenuated in cKO and restored by a TGFB receptor inhibitor (SB431542) administration. Since TGFBR2 and TGFB1 are known miR-21 targets, we suggest that miR-21 transfer from injured neurons to macrophages maintains a pro-inflammatory phenotype via suppression of such an anti-inflammatory pathway. These data support miR-21 inhibition as a possible approach to maintain polarization of DRG macrophages at M2-like state and attenuate neuropathic pain.

Authors

Lynda Zeboudj, George Sideris-Lampretsas, Rita Silva, Sabeha Al-Mudaris, Francesca Picco, Sarah Fox, David Chambers, Marzia Malcangio

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Preconception paternal ethanol exposures induce alcohol-related craniofacial growth deficiencies in fetal offspring
Kara N. Thomas, … , Yudhishtar S. Bedi, Michael C. Golding
Kara N. Thomas, … , Yudhishtar S. Bedi, Michael C. Golding
Published April 11, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI167624.
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Preconception paternal ethanol exposures induce alcohol-related craniofacial growth deficiencies in fetal offspring

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Abstract

Authors

Kara N. Thomas, Nimisha Srikanth, Sanat S. Bhadsavle, Kelly R. Thomas, Katherine N. Zimmel, Alison Basel, Alexis N. Roach, Nicole A. Mehta, Yudhishtar S. Bedi, Michael C. Golding

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Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity
Anna Stokowska, … , Milos Pekny, Marcela Pekna
Anna Stokowska, … , Milos Pekny, Marcela Pekna
Published March 30, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI162253.
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Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity

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Abstract

Despite advances in acute care, ischemic stroke remains a major cause of long-term disability. Approaches targeting both neuronal and glial responses are needed to enhance recovery and improve long-term outcome. The complement C3a receptor (C3aR) is a regulator of inflammation with roles in neurodevelopment, neural plasticity, and neurodegeneration. Using mice lacking C3aR (C3aR–/–) and mice overexpressing C3a in the brain, we uncovered two opposing effects of C3aR signaling on functional recovery after ischemic stroke: inhibition in the acute phase and facilitation in the later phase. Peri-infarct astrocyte reactivity was increased and density of microglia reduced in C3aR–/– mice, C3a overexpression led to the opposite effects. Pharmacological treatment of wild-type mice with intranasal C3a starting 7 days after stroke accelerated recovery of motor function and attenuated astrocyte reactivity without enhancing microgliosis. C3a treatment stimulated global white matter reorganization, increased peri-infarct structural connectivity and upregulated Igf1 and Thbs4 in the peri-infarct cortex. Thus, C3a treatment from day 7 after stroke exerts positive effects on astrocytes and neuronal connectivity while avoiding the deleterious consequences of C3aR signaling during the acute phase. Intranasal administration of C3aR agonists within convenient time window holds translational promise to improve outcome after ischemic stroke.

Authors

Anna Stokowska, Markus Aswendt, Daniel Zucha, Stephanie Lohmann, Frederique Wieters, Javier Moran Suarez, Alison L. Atkins, YiXian Li, Maria Miteva, Julia Lewin, Dirk Wiedermann, Michael Diedenhofen, Åsa Torinsson Naluai, Pavel Abaffy, Lukas Valihrach, Mikael Kubista, Mathias Hoehn, Milos Pekny, Marcela Pekna

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Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies
Xin Chen, … , Darius Ebrahimi-Fakhari, Steven J. Gray
Xin Chen, … , Darius Ebrahimi-Fakhari, Steven J. Gray
Published March 23, 2023
Citation Information: J Clin Invest. 2023. https://doi.org/10.1172/JCI164575.
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Intrathecal AAV9/AP4M1 gene therapy for hereditary spastic paraplegia 50 shows safety and efficacy in preclinical studies

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Abstract

Spastic paraplegia 50 (SPG50) is an ultrarare childhood-onset neurological disorder caused by biallelic loss-of-function variants in the AP4M1 gene. SPG50 is characterized by progressive spastic paraplegia, global developmental delay and subsequent intellectual disability, secondary microcephaly, and epilepsy. Preclinical studies evaluated an adeno-associated virus (AAV)/AP4M1 gene therapy for SPG50. In vitro studies demonstrated that transduction of patient-derived fibroblasts with AAV2/AP4M1 resulted in phenotypic rescue. To evaluate efficacy in vivo, Ap4m1 knockout mice were intrathecally (IT) injected with 5E11, 2.5E11, or 1.25E11 vg doses of AAV9/AP4M1 at postnatal day p7-10 (pre-manifesting cohorts) or p90 (early manifesting cohorts). Age- and dose-dependent effects were observed, with early intervention and higher doses achieving the best therapeutic benefits. In parallel, three toxicology studies in wild-type mice, rats, and non-human primates (NHPs) demonstrated that AAV9/AP4M1 had an acceptable safety profile up to a target human dose of 1E15 vg. Of note, similar degrees of minimal to mild dorsal root ganglia (DRG) toxicity were observed in both rats and NHPs, supporting the use of rats to monitor DRG toxicity in future IT AAV studies. These preclinical results identify an acceptably safe and efficacious dose of IT-administered AAV9/AP4M1, supporting an investigational gene transfer clinical trial to treat SPG50.

Authors

Xin Chen, Thomas Dong, Yuhui Hu, Raffaella De Pace, Rafael Mattera, Kathrin Eberhardt, Marvin Ziegler, Terry Pirovolakis, Mustafa Sahin, Juan S. Bonifacino, Darius Ebrahimi-Fakhari, Steven J. Gray

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DREAM suppression in Huntington’s disease
José Naranjo and colleagues reveal that downregulation of DREAM mediates derepression of ATF6, and this elevation of ATF6 plays an early neuroprotective role in Huntington’s disease…
Published January 11, 2016
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Extra-cerebellar motor symptoms in Angelman’s syndrome
Caroline Bruinsma and colleagues evaluated cerebellar involvement in Angelman’s Syndrome motor deficits…
Published October 20, 2015
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An epigenetic intervention for neurodegenerative diseases
Eva Benito and colleagues demonstrate that SAHA, a histone-deacetylase inhibitor, improves spatial memory and selectively regulates the neuronal epigenome in a mouse model of neurodegeneration…
Published August 17, 2015
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Genetic and environmental interactions in Parkinson’s disease
Alevtina Zharikov and colleagues reveal that interplay between α-synuclein and environmental toxin exposure influences parkinsonian neurodegeneration…
Published June 15, 2015
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TREM2 keeps myelinated axons under wraps
Pietro Poliani, Yaming Wang, and colleagues demonstrate that TREM2 deficiency reduces age-associated expansion of microglia and microglia-dependent remyelination…
Published April 20, 2015
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Synergy among Parkinson’s disease-associated genes
Durga Meka and colleagues demonstrate that crosstalk between parkin and RET maintains mitochondrial integrity and protects dopaminergic neurons…
Published March 30, 2015
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A model of periventricular leukomalacia
Tamar Licht, Talia Dor-Wollman and colleagues demonstrate that specific vulnerability of immature blood vessels surrounding ventricles predisposes to hypoxia-induced periventricular leukomalacia…
Published February 17, 2015
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