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| Open AccessSpatial transcriptomics reveals molecular dysfunction associated with cortical Lewy pathology
The impact of α-synuclein aggregates on neurons has been unclear. Here, the authors identify a Lewy Associated Molecular Dysfunction from Aggregates (LAMDA) signature in inclusion bearing neurons in human brain and a mouse model of α-synucleinopathy.
- Thomas M. Goralski
- , Lindsay Meyerdirk
- & Michael X. Henderson
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Article
| Open AccessUltrastructure of human brain tissue vitrified from autopsy revealed by cryo-ET with cryo-plasma FIB milling
Here the authors report a method for cryogenic electron microscopy imaging of human brain tissue samples directly obtained from autopsy, offering insights into cellular ultrastructure and a tool to study potential pathologic features.
- Benjamin C. Creekmore
- , Kathryn Kixmoeller
- & Yi-Wei Chang
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Article
| Open AccessSKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
Secretory autophagy (SA) plays a crucial role in neuroinflammation-driven neurodegeneration, through SKA2 and FKBP5. SKA2 regulation of SA can inhibit IL-1β release. Its dysfunction leads to neurodegeneration, and is linked to Alzheimer’s disease.
- Jakob Hartmann
- , Thomas Bajaj
- & Nils C. Gassen
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Article
| Open AccessPlasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology
A range of blood-based biomarkers have shown high specificity for Alzheimer’s disease (AD) pathophysiology with phosphorylated-tau (p-tau) being the most promising test. Here, the authors show the utility of plasma p-tau212 in autopsy-confirmed AD and memory clinic patient cohorts.
- Przemysław R. Kac
- , Fernando González-Ortiz
- & Thomas K. Karikari
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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Article
| Open AccessExpression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia
Mutations in profilin 1 (PFN1), which modulates actin dynamics, are associated with ALS. Here the authors show that expression of ALS-PFN1 is sufficient to induce deficits in human microglia-like cells, including impaired phagocytosis and lipid metabolism, and that gain-of-function interactions between ALS-PFN1 and PI3P may underlie these deficits.
- Salome Funes
- , Jonathan Jung
- & Daryl A. Bosco
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Article
| Open AccessHTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species
The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.
- Sheng Chen
- , Anuradhika Puri
- & Meredith E. Jackrel
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Article
| Open AccessA blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Review Article
| Open AccessNeuropathogenesis-on-chips for neurodegenerative diseases
This review focuses on recent advances in on-chip platforms for patient-like in vitro modeling of the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic lateral sclerosis. The authors advocate for broader usage of these human-relevant models in the academic and pharmaceutical fields.
- Sarnai Amartumur
- , Huong Nguyen
- & Chaejeong Heo
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Article
| Open AccessIdentification of four biotypes in temporal lobe epilepsy via machine learning on brain images
Brain imaging-based disease progression modelling is a promising technique for disease stratification. Here the authors characterize distinct ‘trajectories’ of brain atrophy in temporal lobe epilepsy and identify four subtypes with distinct neuroanatomical signatures.
- Yuchao Jiang
- , Wei Li
- & Dongmei An
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Article
| Open AccessNumerosity estimation of virtual humans as a digital-robotic marker for hallucinations in Parkinson’s disease
Virtual reality, robotics and digital online technologies reveal heightened visual overestimation when estimating the number of humans, indexing presence hallucinations in healthy participants and patients with Parkinson’s disease.
- Louis Albert
- , Jevita Potheegadoo
- & Olaf Blanke
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Article
| Open AccessIdentification of gene regulatory networks affected across drug-resistant epilepsies
Epilepsy is a chronic, heterogeneous disease with an urgent need for novel therapies. Here, the authors show a systematic comparison of the global molecular signature of refractory epilepsies elucidating the key mechanisms of the disease pathology.
- Liesbeth François
- , Alessia Romagnolo
- & Eleonora Aronica
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Article
| Open AccessPCDHA9 as a candidate gene for amyotrophic lateral sclerosis
Genetic mutations are found in only 15% of sporadic ALS. Here, authors identify PCDHA9 as a candidate ALS gene and elucidate detailed underlying pathogenesis using mice with Pcdhα9 mutations that develop typical ALS phenotype and hallmark pathology.
- Jie Zhong
- , Chaodong Wang
- & Zhiheng Xu
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Article
| Open AccessFUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease
Dysfunction of Fused in Sarcoma (FUS) leads to increased mitochondrial DNA (mtDNA) damage, mutations, and mitochondrial dysfunction. This study shows that FUS collaborates with mtDNA Ligase IIIα to maintain mtDNA repair and integrity.
- Manohar Kodavati
- , Haibo Wang
- & Muralidhar L. Hegde
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Article
| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessAn artificial protein modulator reprogramming neuronal protein functions
Direct modulation of protein by artificial catalysts as enzyme mimetics remains hindered by the lack of highly efficient catalytic centers. Here, the authors present the development of artificial protein modulators (APROMs) with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein.
- Peihua Lin
- , Bo Zhang
- & Daishun Ling
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Article
| Open AccessProfiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation.
- Aletta M. R. van den Bosch
- , Marlijn van der Poel
- & Jörg Hamann
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Article
| Open AccessQuantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
In tauopathies, the microtubule-associated protein tau is hyperphosphorylated and aggregated. Here the authors identified a polypharmacological small molecule that inhibits aggregation, reduces phosphorylation, and restores microtubule interaction of tau.
- Luca Pinzi
- , Christian Conze
- & Roland Brandt
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Article
| Open AccessStalled translation by mitochondrial stress upregulates a CNOT4-ZNF598 ribosomal quality control pathway important for tissue homeostasis
Ribosome associated quality control (RQC) is a new area of biological investigation with emerging connection to a broad range of diseases. Here authors show that mitochondrial stress can upregulate a new RQC pathway important for tissue homeostasis.
- Ji Geng
- , Shuangxi Li
- & Bingwei Lu
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Article
| Open AccessDeep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome
Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined and the pathophysiology unknown. Here, the authors conduct deep phenotyping of a cohort of PI-ME/CFS patients.
- Brian Walitt
- , Komudi Singh
- & Avindra Nath
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Article
| Open AccessIntegrating single-cell and spatially resolved transcriptomic strategies to survey the astrocyte response to stroke in male mice
Astrocytes adopt diverse states in response to brain injuries. Here, the authors develop a platform for spatially resolved, single-cell transcriptomics and proteomics, called tDISCO (tissue-digital microfluidic isolation of single cells for -Omics) to uncover the spatial boundaries of molecularly distinct reactive astrocyte populations in stroke.
- Erica Y. Scott
- , Nickie Safarian
- & Maryam Faiz
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Article
| Open AccessA transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration
The etiology of TDP-43 proteinopathy in ALS and FTD is complex. Here, the authors show that prior to disease onset in the rNLS8 mouse model, cortex neurons elicit a transient increase in protective chaperones that combat TDP-43 aggregation.
- Rebecca San Gil
- , Dana Pascovici
- & Adam K. Walker
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
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Article
| Open AccessThe secondary somatosensory cortex gates mechanical and heat sensitivity
How and where somatosensory information is encoded in the cortex is unclear and important for developing new pain therapies. Here the authors show a crucial role for the secondary somatosensory cortex (S2) in accurate perception of sensory stimuli.
- Daniel G. Taub
- , Qiufen Jiang
- & Clifford J. Woolf
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Article
| Open AccessTransient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy
Epileptic seizures need better treatments. Here, the authors show that seizure intensity is predicted and controlled by pre-seizure activity of hypothalamic orexin cells, and can be reduced by a hypothalamic deep brain stimulation.
- Han-Tao Li
- , Paulius Viskaitis
- & Denis Burdakov
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Article
| Open AccessAmyloid-β aggregates activate peripheral monocytes in mild cognitive impairment
Alzheimer’s Disease (AD) is commonly preceded by a prodromal period. Here, the authors report the presence of large plasma Aβ aggregates from patients with mild cognitive impairment, which associate with low level AD-like brain pathology as observed by 11C-PiB PET and 18F-FTP PET and lowered CD18-rich monocytes.
- Kristian Juul-Madsen
- , Peter Parbo
- & Thomas Vorup-Jensen
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Article
| Open AccessSex dependence of opioid-mediated responses to subanesthetic ketamine in rats
In rats, functional ultrasound imaging reveals that blocking opioid receptors modulates the effects of subanesthetic ketamine on neural activity in males but not in females, with parallel changes in ketamine’s effects on brain structure and behavior.
- Tommaso Di Ianni
- , Sedona N. Ewbank
- & Raag D. Airan
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Article
| Open AccessiPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity
PACS1 syndrome is a neurodevelopmental disorder resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). Here the authors use cortical organoids to investigate the impact of this variant on neurodevelopment.
- Lauren Rylaarsdam
- , Jennifer Rakotomamonjy
- & Alicia Guemez-Gamboa
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Article
| Open AccessA mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release
The role of mesocortical pathway in pain modulation is poorly understood. Here, authors show in mice that enhancing ventral tegmental area to prefrontal cortex glutamatergic activity alleviates neuropathic pain independently of dopamine co-release.
- Miao Li
- & Guang Yang
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Article
| Open AccessDeath Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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Article
| Open AccessAcetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice
Traditional systematic anti-seizure treatments alter brain-wide activity and often carry significant side effects. The authors engineered an inhibitory, acetylcholine receptor-based, chemogenetic tool to suppress targeted neurons, enabling control of chronic seizures in mice.
- Quynh-Anh Nguyen
- , Peter M. Klein
- & Ivan Soltesz
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Article
| Open AccessHigh-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Using an unbiased phenotypic cell-based high-throughput screen, the authors identify and characterize a small molecule, BCH-HSP-C01, that restores aberrant protein trafficking in neuronal models of adapter protein complex 4 deficiency.
- Afshin Saffari
- , Barbara Brechmann
- & Mustafa Sahin
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Article
| Open AccessDisruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
The protein DJ1, encoded by the PARK7 gene, is causally linked to development of early-onset PD. Here the authors observed that the loss of DJ1 function in midbrain organoids led to astrocyte dysfunction, impairing protein clearance, accumulation of α-synuclein.
- Gustavo Morrone Parfitt
- , Elena Coccia
- & Tim Ahfeldt
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Article
| Open AccesshnRNP A1 dysfunction alters RNA splicing and drives neurodegeneration in multiple sclerosis (MS)
HnRNP A1 dysfunction is associated with neurodegeneration in multiple sclerosis (MS). Herein, advanced RNA sequencing and CLIPseq of MS brains and relevant models demonstrated that hnRNP A1 binding of target RNAs and RNA splicing were altered, precipitating neurodegeneration.
- Hannah E. Salapa
- , Patricia A. Thibault
- & Michael C. Levin
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Article
| Open AccessChronic oxytocin administration stimulates the oxytocinergic system in children with autism
Intranasal administration of oxytocin is increasingly considered as a new therapeutic option for alleviating stress and social problems in children with autism. Here, important insights are provided into how repeated administration of oxytocin influences the functioning of one’s own oxytocin system.
- Matthijs Moerkerke
- , Nicky Daniels
- & Kaat Alaerts
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Article
| Open AccessANKS1B encoded AIDA-1 regulates social behaviors by controlling oligodendrocyte function
Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome. Here the authors show this syndrome is associated with impaired white matter integrity, and that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function.
- Chang Hoon Cho
- , Ilana Vasilisa Deyneko
- & Bryen A. Jordan
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Article
| Open AccessSynaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration
Translational neurodegeneration needs characterisation of the downstream consequences of synaptic loss. A multimodal imaging approach reveals that synaptic loss affects clinical severity via reduced connectivity in frontotemporal lobar degeneration.
- David J. Whiteside
- , Negin Holland
- & James B. Rowe
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Article
| Open AccessUSP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder
This study uncovers the role of epigenetic H2A monoubiquitination in the mouse brain’s response to chronic cocaine use. It also identifies genetic variations in humans linked to H2A monoubiquitination, modifying susceptibility to cocaine addiction and aggression, and paving the way for tailored treatments.
- Julian Cheron
- , Leonardo Beccari
- & Alban de Kerchove d’Exaerde
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Article
| Open AccessEfficient generation of a self-organizing neuromuscular junction model from human pluripotent stem cells
Here, Urzi et al. pioneered a 2D self-organizing neuromuscular junction (soNMJ) model from human pluripotent stem cells, with implications for neuromuscular disease modeling and drug screening approaches.
- Alessia Urzi
- , Ines Lahmann
- & Mina Gouti
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Article
| Open AccessD-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia
Modulation of NMDA receptors via D-serine has been investigated as therapeutic strategy in schizophrenia. Here the authors show that D-serine rescues synaptic and intrinsic inhibitory control of cingulate pyramidal neurons, via modulation of parvalbumin neuron excitability, in a mouse model of neurodevelopmental cognitive dysfunction.
- Xiao-Qin Zhang
- , Le Xu
- & Hao-Wei Shen
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Article
| Open AccessLate gene therapy limits the restoration of retinal function in a mouse model of retinitis pigmentosa
Is there a critical period to deliver gene therapies in photoreceptor degeneration? Using a mouse model of retinitis pigmentosa, the authors show that once 70% of rods are lost, gene replacement fails to restore normal retinal output.
- Miranda L. Scalabrino
- , Mishek Thapa
- & Greg D. Field
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Article
| Open AccessEnhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
The differentiation of human pluripotent stem cells into dopaminergic neurons is challenging. Here, the authors developed lineage-restricted undifferentiated stem cells, which have an enhanced ability for differentiating into dopaminergic neurons.
- Muyesier Maimaitili
- , Muwan Chen
- & Mark Denham
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Article
| Open AccessPhox2b-expressing neurons contribute to breathing problems in Kcnq2 loss- and gain-of-function encephalopathy models
Kcnq2 disfunction can cause developmental and epileptic encephalopathy (DEE). Here, authors show loss or gain of Kcnq2 function in Phox2b-expressing neurons disrupts breathing, thus identifying these cells as a likely basis for DEE breathing problems.
- J. Soto-Perez
- , C. M. Cleary
- & D. K. Mulkey
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Article
| Open AccessInvestigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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Article
| Open AccessEnhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice
Ketamine produces rapid antidepressant effects, but the mechanism involved is not fully understood. Here the authors show that ketamine enhances glutamatergic neurotransmission and produces rapid antidepressant-like effects though recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice.
- Shi-Ge Xue
- , Jin-Gang He
- & Jian-Guo Chen
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Article
| Open AccessOpposing brain signatures of sleep in task-based and resting-state conditions
The associations between sleep, depression and brain activity are not well understood. Here, the authors show patterns of brain activity associated with insomnia and depression resemble those found in people who sleep less, but only under cognitive load. At rest, these activation patterns are hyperconnected and resemble those found in longer sleepers.
- Mohamed Abdelhack
- , Peter Zhukovsky
- & Daniel Felsky
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Article
| Open AccessEndogenous noise of neocortical neurons correlates with atypical sensory response variability in the Fmr1−/y mouse model of autism
Enhanced variability is a hallmark of atypical sensory processing in autism. Here, focusing on variability of neocortical tactile responses in mice, the authors explore the role of endogenous noise sources in neural processing in a model of autism.
- Arjun A. Bhaskaran
- , Théo Gauvrit
- & Andreas Frick
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