Featured
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Article
| Open AccessStructural basis of epilepsy-related ligand–receptor complex LGI1–ADAM22
LGI1 is an epilepsy-related gene that encodes a secreted neuronal protein. Here the authors present the crystal structure of LGI1 bound to its receptor ADAM22, which provides structural insights into epilepsy-causing LGI1 mutations and might facilitate the development of novel anti-epilepsy drugs.
- Atsushi Yamagata
- , Yuri Miyazaki
- & Shuya Fukai
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Article
| Open AccessTRPV1 SUMOylation regulates nociceptive signaling in models of inflammatory pain
SUMOylation is a post translational modification. Here the authors show that TRPV1, which conveys thermal nociception, is SUMOylated in DRGs in inflammatory conditions and contributes to pain behavior in mice.
- Yan Wang
- , Yingwei Gao
- & Yong Li
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Article
| Open AccessNeuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease
Sphingosine kinase (SphK) converts sphingosine into lipids, and is implicated in inflammation. Here the authors show that SphK1 functions as an acetyltransferase, regulates microglial phagocytosis and is reduced in a model of Alzheimer’s Disease, such that its restoration ameliorates pathology
- Ju Youn Lee
- , Seung Hoon Han
- & Hee Kyung Jin
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Article
| Open AccessGenome-wide association study of depression phenotypes in UK Biobank identifies variants in excitatory synaptic pathways
The UK Biobank provides data for three depression-related phenotypes. Here, Howard et al. perform a genome-association study for broad depression, probable major depressive disorder (MDD) and hospital record-coded MDD in up to 322,580 UK Biobank participants which highlights excitatory synaptic pathways.
- David M. Howard
- , Mark J. Adams
- & Andrew M. McIntosh
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Article
| Open AccessGABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease
Cholinergic interneurons of the striatum are involved reward-related behaviors and have been implicated in Parkinson’s disease. Here the authors report that half of cholinergic neurons co-release acetylcholine and GABA, and study the role of these neurons in a model of Parkinson’s Disease.
- N. Lozovaya
- , S. Eftekhari
- & C. Hammond
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Article
| Open AccessThe human cortex possesses a reconfigurable dynamic network architecture that is disrupted in psychosis
Temporal changes in brain dynamics are linked with cognitive abilities, but neither their stability nor relationship to psychosis is clear. Here, authors describe the dynamic neural architecture in healthy controls and patients with psychosis and find that they are stable over time and can predict psychotic symptoms.
- Jenna M. Reinen
- , Oliver Y. Chén
- & Avram J. Holmes
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Article
| Open AccessA common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers
Disruption of the ubiquitin proteasome system (UPS) is often associated with neurodegenerative diseases. Here the authors demonstrate the existence of a general mechanism of proteasomal impairment triggered by a specific protein oligomer structure, irrespective of its protein constituent.
- Tiffany A. Thibaudeau
- , Raymond T. Anderson
- & David M. Smith
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Article
| Open AccessPredicting the spatiotemporal diversity of seizure propagation and termination in human focal epilepsy
A major goal of epilepsy research is understanding the spatiotemporal dynamics of seizure. Here, the authors extend the Epileptor neural mass model into a neural field model, in order to provide a unified and patient-specific model of seizure initiation, propagation, and termination.
- Timothée Proix
- , Viktor K. Jirsa
- & Wilson Truccolo
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Article
| Open AccessVesicular glutamate release from central axons contributes to myelin damage
Neuronal activity can lead to vesicular release of glutamate. Here the authors demonstrate that vesicular release of glutamate occurs in axons during ischemic conditions, and that an allosteric modulator of GluN2C/D is protective in models of ischemic injury.
- Sean Doyle
- , Daniel Bloch Hansen
- & Robert Fern
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Article
| Open AccessInhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice
Sensitisation of dorsal root ganglia neurons contributes to neuropathic pain. Here the authors demonstrate the cytokine FL contributes to sensitisation of DRGs via its receptor FLT3 expressed on neurons, and identify a novel FLT3 inhibitor that attenuates neuropathic pain in mice.
- Cyril Rivat
- , Chamroeun Sar
- & Jean Valmier
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Article
| Open AccessAberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy
Mutations in glycyl-tRNA synthetase (GlyRS) cause Charcot-Marie-Tooth disease, a neuromuscular disorder characterized by axonal degeneration. Here the authors show that mutant GlyRS interacts with histone deacetylase 6, resulting in increased deacetylation of α-tubulin and axonal transport deficits.
- Zhongying Mo
- , Xiaobei Zhao
- & Xiang-Lei Yang
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Article
| Open AccessDisease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties
N-methyl-d-aspartate-receptors (NMDARs) are glutamate receptors critical for synaptic transmission, plasticity, and cognition. Here, the authors look at four neurodevelopmental disease-related mutations of NMDAR, gaining insight into binding of Mg2+ and mechanism of memantine, an NMDAR antagonist.
- Laura Fedele
- , Joseph Newcombe
- & Trevor G. Smart
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Article
| Open AccessCardiolipin exposure on the outer mitochondrial membrane modulates α-synuclein
Cardiolipin is a phospholipid component of the inner mitochondrial membrane. Here the authors demonstrate that cardiolipin interacts with mutant α-synuclein, and that impaired cardiolipin function can lead to spread of α-synuclein between neurons.
- Tammy Ryan
- , Vladimir V. Bamm
- & Scott D. Ryan
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Article
| Open AccessVentromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder
Loss of muscle tone is a distinguishing feature of paradoxical or REM sleep (PS) and is disrupted in REM sleep behavior disorder. Here the authors report that GABA/glycine inhibitory neurons in the ventromedial medulla are essential for producing PS muscle atonia without affecting PS quantity.
- Sara Valencia Garcia
- , Frédéric Brischoux
- & Patrice Fort
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Article
| Open AccessTargeting Tyro3 ameliorates a model of PGRN-mutant FTLD-TDP via tau-mediated synaptic pathology
Progranulin (PGRN) mutations cause frontotemporal lobe dementia with TDP-43 pathology. Here the authors develop a mutant PGRN knock-in mouse model of the disease, and show that Tyro3, a tyrosine kinase membrane receptor that acts upstream of PKC and MAPK, is inhibited by PGRN which contributes to pathology in this model.
- Kyota Fujita
- , Xigui Chen
- & Hitoshi Okazawa
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Article
| Open AccessC9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
Repeat expansion mutation in C9ORF72 is the most common cause of familial ALS. Here, the authors generate motor neurons from cells of patients with C9ORF72 mutations, and characterize changes in gene expression in these motor neurons compared to genetically corrected lines, which suggest that glutamate receptor subunit GluA1 is dysregulated in this form of ALS.
- Bhuvaneish T. Selvaraj
- , Matthew R. Livesey
- & Siddharthan Chandran
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Article
| Open AccessImpaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation
Abnormal cytoplasmic aggregates of FUS are a hallmark of some forms of amyotrophic lateral sclerosis (ALS). Here, using neurons derived from patients with FUS-ALS, the authors demonstrate that impairment of PARP-dependent DNA damage signaling is an event that occurs upstream of neurodegeneration and cytoplasmic aggregate formation in FUS-ALS.
- Marcel Naumann
- , Arun Pal
- & Andreas Hermann
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Article
| Open AccessA mouse model of autism implicates endosome pH in the regulation of presynaptic calcium entry
The Na+/H+ exchanger NHE9 is proposed to regulate the H+ electrochemical gradient across endosomal membranes. Here, the authors find that NHE9 knockout mice show autism spectrum disorder-like behaviors and disrupted synaptic vesicle exocytosis due to impaired presynaptic calcium entry.
- Julie C. Ullman
- , Jing Yang
- & Robert H. Edwards
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Article
| Open AccessNeuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures
Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.
- André M. Miranda
- , Zofia M. Lasiecka
- & Gilbert Di Paolo
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Article
| Open AccessGranulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine
Cocaine addiction is accompanied by dysfunction in neural circuits related to reward, but it is unclear how these adaptations occur. Here, authors identify granulocyte-colony stimulating factor as a potent mediator of cocaine-induced adaptations, and show that it can alter the motivation for cocaine.
- Erin S. Calipari
- , Arthur Godino
- & Drew D. Kiraly
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Article
| Open AccessBrain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects
One challenge in drug screening for neurological disorders is how to accurately capture disease pathology and side effects. Here, the authors developed a multi-channel recording platform based on a zebrafish genetic model of epilepsy to screen for antiepileptic drugs.
- Peter M. Eimon
- , Mostafa Ghannad-Rezaie
- & Mehmet Fatih Yanik
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Article
| Open AccessSynaptotagmin-11 is a critical mediator of parkin-linked neurotoxicity and Parkinson’s disease-like pathology
Mutations in the parkin, an ubiquitin ligase, are linked to Parkinson’s disease. Here the authors show that synaptotagmin-11 is a parkin substrate and that its upregulation affects dopamine release, triggers degeneration, and causes motor impairment.
- Changhe Wang
- , Xinjiang Kang
- & Zhuan Zhou
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Article
| Open AccessMulti-day rhythms modulate seizure risk in epilepsy
The ability to identify periods of heightened seizure risk could enable new treatments for patients with epilepsy. Here, the authors describe long term EEG recordings from 37 patients which allow them to identify multi-day fluctuations in interictal activity.
- Maxime O. Baud
- , Jonathan K. Kleen
- & Vikram R. Rao
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Article
| Open AccessNetwork connectivity determines cortical thinning in early Parkinson’s disease progression
In Parkinson’s disease (PD), neurodegeneration spreads from the brainstem to the cerebral cortex. Here, in a longitudinal study of PD patients, the authors found that cortical thinning followed neural connectivity from a “disease reservoir”.
- Y. Yau
- , Y. Zeighami
- & A. Dagher
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Article
| Open AccessExcitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1
Excitotoxicity due to excessive glutamate release causes oxidative stress and neuronal death, and is a feature of many brain diseases. Here the authors show that protein kinase D1 is inactivated by excitotoxicity in a model of stroke and that its activation can be neuroprotective.
- Julia Pose-Utrilla
- , Lucía García-Guerra
- & Teresa Iglesias
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Article
| Open AccessThe sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission
The dopamine transporter (DAT), a regulator of dopamine homeostasis in the brain, and sigma-1 receptor (σ1R), an endoplasmic reticulum membrane protein, are both implicated in drug addiction. In this work, the authors investigate how σ1R modulates DAT response to methamphetamine.
- Danielle O. Sambo
- , Min Lin
- & Habibeh Khoshbouei
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Article
| Open AccessMidbrain circuit regulation of individual alcohol drinking behaviors in mice
Mice exposed to a two-bottle alcohol choice paradigm can be divided into high and low drinking groups. Here, the authors show that stimulating VTA neurons to induce higher phasic activity patterns that are observed in low alcohol drinking mice, suppresses alcohol drinking in mice that are high alcohol drinking.
- Barbara Juarez
- , Carole Morel
- & Ming-Hu Han
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Article
| Open AccessHippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task
Theta- and gamma-frequency oscillatory synchrony correlates with spatial working memory performance. Here the authors report increases in theta-gamma cross-frequency coupling as a compensatory mechism associated with better working memory performance in models of cognitive dysfunction in mice.
- Makoto Tamura
- , Timothy J. Spellman
- & Joshua A. Gordon
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Article
| Open AccessBri2 BRICHOS client specificity and chaperone activity are governed by assembly state
The BRICHOS domain is a chaperone that can act against amyloid-β peptide fibril formation and non-fibrillar protein aggregation. Here the authors use a multidisciplinary approach and show that the Bri2 BRICHOS domain has qualitatively different chaperone activities depending on its quaternary structure.
- Gefei Chen
- , Axel Abelein
- & Jan Johansson
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Article
| Open AccessEndocytosis regulates TDP-43 toxicity and turnover
Impaired turnover of TDP-43 by impaired autophagy or proteasomal function have been suggested to be the cause of TDP-43 accumulation, a hallmark of ALS. Here the authors demonstrate that endocytosis is also important for regulating TDP-43 turnover and toxicity.
- Guangbo Liu
- , Alyssa N. Coyne
- & J. Ross Buchan
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Article
| Open AccessRAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response
A nucleotide repeat expansion in C9orf72 is a common genetic cause of neurodegenerative disorders. Here, the authors provide insight into the molecular mechanism by which this repeat undergoes Repeat-Associated Non-AUG (RAN) translation, implicating the integrated stress response and eIF2α phosphorylation.
- Katelyn M. Green
- , M. Rebecca Glineburg
- & Peter K. Todd
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Article
| Open AccessDevelopmental YAPdeltaC determines adult pathology in a model of spinocerebellar ataxia type 1
Ataxin-1, linked to spinocerebellar ataxia type 1, is known to interact with the orphan nuclear receptor RORα. Here, Fujita and colleagues show that genetic supplementation of RORα-interacting protein YAPdeltaC during early development can rescue the adult pathologies of SCA1 mouse model.
- Kyota Fujita
- , Ying Mao
- & Hitoshi Okazawa
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Article
| Open AccessDynamic disorganization of synaptic NMDA receptors triggered by autoantibodies from psychotic patients
Autoantibodies are found in neuropsychiatric conditions but without clear cellular mechanism and disease relevance. This study shows higher prevalence of autoantibodies against NMDAR receptors in schizophrenia patients, and patient-associated antibody can alter synaptic receptor trafficking and plasticity.
- Julie Jézéquel
- , Emily M. Johansson
- & Laurent Groc
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Article
| Open AccessExosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma
Exosomes are known to contain microRNAs (miRs). Here the authors show that dorsal root ganglion neurons release exosomes containing miR-21-5p, which contributes to inflammatory cell recruitment following peripheral nerve injury.
- Raffaele Simeoli
- , Karli Montague
- & Marzia Malcangio
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Article
| Open AccessDiscovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes
The Alzheimer protein Tau interacts with biological membranes, but the role of these interactions in regulating Tau function in health and disease remains unexplored. Here, the authors report on the discovery and characterization of neurotoxic oligomeric protein/phospholipid complexes.
- Nadine Ait-Bouziad
- , Guohua Lv
- & Hilal A. Lashuel
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Article
| Open AccessImpairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses
Cholinergic neurons in the diagonal band of Broca degenerate early in Alzheimer’s disease. Here the authors show that in healthy mice, these cholinergic inputs innervate newborn neurons in the hippocampus, and that loss of this innervation in an Alzheimer’s disease model leads to impairments in spatial memory.
- Houze Zhu
- , Huanhuan Yan
- & Youming Lu
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Article
| Open AccessTrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response
The precise mechanism for the sustained antidepressant action of ketamine is unclear. This study shows ketamine can promote neuronal differentiation via TrkB-ERK activation in mice and the sustained behavioral effect is attenuated when adult neurogenesis is blocked, but extended when it is enhanced.
- Zhenzhong Ma
- , Tong Zang
- & Luis F. Parada
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Article
| Open AccessNitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism
Human MEF2C haploinsufficiency results in Autism Spectrum Disorder (ASD), but it is unclear if the same is true in mice. Here, the authors show that Mef2c +/− mice have behavioral defects and neuronal abnormalities similar to ASD, and symptoms can be ameliorated with the new drug, NitroSynapsin.
- Shichun Tu
- , Mohd Waseem Akhtar
- & Nobuki Nakanishi
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Article
| Open AccessER-associated degradation regulates Alzheimer’s amyloid pathology and memory function by modulating γ-secretase activity
Endoplasmic-reticulum associated degradation (ERAD) regulates protein homeostasis. Here the authors identify an ERAD component membralin, and show that it interacts with a member of the γ-secretase complex to regulate β-amyloid (Aβ) pathology and memory deficits in an Alzheimer’s disease model.
- Bing Zhu
- , LuLin Jiang
- & Huaxi Xu
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Article
| Open AccessNeuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
The APOE4 allele is the leading risk factor for late-onset Alzheimer’s disease, but how it might contribute to the disease is not clear. Here the authors show that a mouse expressing the human APOE4 allele displays hyperactivity in the entorhinal cortex due to a decreased inhibitory tone, which may in part explain accelerated Alzheimer’s pathology in APOE4 carriers.
- Tal Nuriel
- , Sergio L. Angulo
- & Karen E. Duff
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Article
| Open AccessIdentification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease
Cerebrovascular changes and astrogliosis occur in Alzheimer’s disease (AD). Using an in vivo phage display technique, the authors identified a peptide that upon systematic administration, can home to brain endothelial cells and astrocytes in mouse models of AD at the early stages of the disease.
- Aman P. Mann
- , Pablo Scodeller
- & Erkki Ruoslahti
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Article
| Open AccessPINK1-mediated phosphorylation of LETM1 regulates mitochondrial calcium transport and protects neurons against mitochondrial stress
Mutations in the mitochondrial kinase PINK1 result in familial Parkinson’s disease. Here the authors show that LETM1, a mitochondrial inner membrane protein, is a substrate of PINK1 that regulates Ca2+ handling in mitochondria in response to mitochondrial toxins.
- En Huang
- , Dianbo Qu
- & David S. Park
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Article
| Open AccessSpermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome
Mutations in spermine synthase lead to Snyder-Robinson syndrome, a form of intellectual disability syndrome. Here the authors develop a Drosophila model of this disease, and show that lysosomal dysfunction and oxidative stress contribute to the morphological phenotype in these flies, as well as to cellular deficits in cells derived from patients.
- Chong Li
- , Jennifer M. Brazill
- & R. Grace Zhai
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Article
| Open AccessEarliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity
Abnormal levels of Aβ42 in the cerebrospinal fluid occur prior to a positive amyloid PET scan in the brain of individuals with Alzheimer’s disease and here the authors use this temporal pattern to identify individuals with very early stage AD. They show that Aβ fibrils start to accumulate in some of the regions of the default mode network and affect brain connectivity before neurodegeneration occurs.
- Sebastian Palmqvist
- , Michael Schöll
- & Oskar Hansson
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Article
| Open AccessPlekhg5-regulated autophagy of synaptic vesicles reveals a pathogenic mechanism in motoneuron disease
Accumulating evidence suggests that disruption of autophagy is associated with neurodegeneration. Here the authors show that Plekhg5 acts as a GEF for Rab26, a small GTPase that promotes the autophagy of synaptic vesicles in neurons; mice lacking Plekgh5 develop late-onset motoneuron degeneration.
- Patrick Lüningschrör
- , Beyenech Binotti
- & Michael Sendtner
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Article
| Open AccessOptogenetically stimulating intact rat corticospinal tract post-stroke restores motor control through regionalized functional circuit formation
Existing methods to improve motor function after stroke include non-specific neuromodulatory approaches. Here the authors use an automated method of analysis of reaching behaviour in rodents to show that optogenetic stimulation of intact corticospinal tract fibres leads to restoration of prior motor functions, rather than compensatory acquisition of new movements.
- A. S. Wahl
- , U. Büchler
- & M. E. Schwab
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Article
| Open AccessA neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models
Astrocytes can have protective or detrimental effects on neurons during injury, but the molecular mechanisms that determine these different states are unresolved. Here the authors identify a pathway via neuronal EphB1 that induces neuroprotective signalling in astrocytes through ephrin-B1 mediated STAT3 activation, which is impaired in models of amyotrophic lateral sclerosis.
- Giulia E. Tyzack
- , Claire E. Hall
- & András Lakatos
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Article
| Open AccessPerturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior
Functional consequence of transient delay in neuronal migration is unclear. This study shows that Wnt/C-Kit signaling regulates radial migration in rat somatosensory cortex, and that transient delay of L2/3 neuronal migration leads to interhemispheric connectivity alteration and abnormal social behavior.
- Riccardo Bocchi
- , Kristof Egervari
- & Jozsef Z. Kiss
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Article
| Open AccessLimiting habenular hyperactivity ameliorates maternal separation-driven depressive-like symptoms
Early-life stress primes depression in adulthood. This study shows that early maternal separation leads to lateral habenula (LHb) hyperactivity and causes depressive-like phenotypes, the latter being reversible when LHb hyperactivity is reduced chemogenetically or through deep-brain stimulation.
- Anna Tchenio
- , Salvatore Lecca
- & Manuel Mameli
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