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| Open AccessBiPOLES is an optogenetic tool developed for bidirectional dual-color control of neurons
Currently, bidirectional control of activity in the same neurons in the same experiment is difficult. Here the authors report a Bidirectional Pair of Opsins for Light-induced Excitation and Silencing, BiPOLES, which they use in a range of organisms including worms, fruit flies, mice and ferrets.
- Johannes Vierock
- , Silvia Rodriguez-Rozada
- & J. Simon Wiegert
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Article
| Open AccessGenetic dissection identifies Necdin as a driver gene in a mouse model of paternal 15q duplications
Duplication of chromosome 15q11-q13 is associated with autism spectrum disorder (ASD). Here, the authors show that in mice paternal Dup15q results in ASD-like neuronal and behavioural impairment driven by Necdin.
- Kota Tamada
- , Keita Fukumoto
- & Toru Takumi
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Article
| Open AccessConservation and divergence of vulnerability and responses to stressors between human and mouse astrocytes
Astrocytes are important players in brain development, homeostasis, and disease. Here, the authors compare the transcriptional profiles of human and mouse astrocytes. They report species-specific susceptibility to oxidative stress and response to hypoxic and inflammatory conditions.
- Jiwen Li
- , Lin Pan
- & Ye Zhang
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Article
| Open AccessThe Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery.
- Feng Li
- , Tsz Y. Lo
- & Yuanquan Song
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Article
| Open AccessSaturated free fatty acids and association with memory formation
Changes in poly-unsaturated free fatty acids (FFAs) have been associated with LTP. Here, using lipidomics analysis the authors characterise FFA changes in the rat brain associated with fear conditioning, and demonstrate that increases in saturated FFAs represent the major change.
- Tristan P. Wallis
- , Bharat G. Venkatesh
- & Frédéric A. Meunier
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Article
| Open AccessTET1-mediated DNA hydroxymethylation regulates adult remyelination in mice
Myelin formation is regulated by epigenetic mechanisms and ensures proper neuronal function during development and after demyelination. Here, the authors show that TET1, a DNA hydroxymethylase, regulates myelin repair in adult mice, but is defective with aging.
- Sarah Moyon
- , Rebecca Frawley
- & Patrizia Casaccia
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Article
| Open AccessPhospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease
Microglia can clear amyloid plaques in Alzheimer’s disease. Here, the authors show that specific isoforms of the phospholipid forming APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer’s disease.
- Nicholas F. Fitz
- , Kyong Nyon Nam
- & Radosveta Koldamova
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Article
| Open AccessNon-productive angiogenesis disassembles Aß plaque-associated blood vessels
Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.
- Maria I. Alvarez-Vergara
- , Alicia E. Rosales-Nieves
- & Alberto Pascual
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Article
| Open AccessTanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons
Alterations of the mTOR signalling pathway are associated with neurodevelopmental defects. Regulators of the mTOR kinase activity are not fully described. Here, the authors show that Tanc2, a scaffolding protein, acts as a direct inhibitor of mTOR kinase activity in the developing mouse brain and cultured human neurons.
- Sun-Gyun Kim
- , Suho Lee
- & Eunjoon Kim
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Article
| Open AccessSingle nucleus RNA-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord
The full heterogeneity and different functional roles of cholinergic neurons in the adult spinal cord remain to be defined. Here the authors develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, as well as visceral and skeletal motor neurons.
- Mor R. Alkaslasi
- , Zoe E. Piccus
- & Claire E. Le Pichon
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Article
| Open AccessGeneration of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.
- David Baglietto-Vargas
- , Stefania Forner
- & Frank M. LaFerla
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Article
| Open AccessNeurexins regulate presynaptic GABAB-receptors at central synapses
Neurexins are evolutionarily conserved cell adhesion molecules that tune synapse formation and specification. Here the authors show that neurexins play similar roles in regulating presynaptic GABAB receptors at multiple CNS synapses.
- Fujun Luo
- , Alessandra Sclip
- & Thomas C. Südhof
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Article
| Open AccessAdenosine integrates light and sleep signalling for the regulation of circadian timing in mice
Sleep pressure and circadian rhythms influence one another. However, the regulatory mechanisms are unclear. Here, the authors show that adenosine A1/A2A receptor antagonists, such as caffeine, shift circadian rhythms and enhance the effects of light, providing a molecular link between sleep pressure and circadian rhythm.
- Aarti Jagannath
- , Norbert Varga
- & Sridhar R. Vasudevan
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Article
| Open AccessA conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons
SFPQ is a splicing factor and its mutations are associated to amyotrophic lateral sclerosis (ALS) patients. Here, the authors show that SFPQ represses the use of pathogenic cryptic last exons in zebrafish, mouse and human cells.
- Patricia M. Gordon
- , Fursham Hamid
- & Corinne Houart
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Article
| Open AccessTDP-43 and PINK1 mediate CHCHD10S59L mutation–induced defects in Drosophila and in vitro
Mutations in CHCHD10 can cause amyotrophic lateral sclerosis and frontotemporal dementia. The authors generate mutant Drosophila and HeLa cells to study the underlying mechanisms of CHCHD10S59L -induced degeneration and show it is mediated by TDP-43 and PINK1 pathways.
- Minwoo Baek
- , Yun-Jeong Choe
- & Nam Chul Kim
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Article
| Open AccessATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking
The molecular mechanisms mediating nociception are unclear. Here, the authors show that the Activating Transcription Factor 4 (ATF4) is important for the response to heat nociception in mice and ATF4 role in mediating protein trafficking in dorsal root ganglion neurons.
- Man-Xiu Xie
- , Xian-Ying Cao
- & Xiao-Long Zhang
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Article
| Open AccessMolecular correlates of muscle spindle and Golgi tendon organ afferents
Coordinated movement critically depends on sensory feedback from muscle spindles (MSs) and Golgi tendon organs (GTOs) but the afferents supplying this proprioceptive feedback have remained genetically inseparable. Here the authors use single cell transcriptome analysis to reveal the molecular basis of MS (groups Ia and II) and GTO (group Ib) afferent identities in the mouse.
- Katherine M. Oliver
- , Danny M. Florez-Paz
- & Joriene C. de Nooij
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Article
| Open AccessInteraction of 7SK with the Smn complex modulates snRNP production
The noncoding RNA 7SK controls the transcription of mRNAs. Here, the authors show that the 7SK complex interacts with the Smn complex, suggesting crosstalk between transcription and snRNP assembly.
- Changhe Ji
- , Jakob Bader
- & Michael Briese
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Article
| Open AccessDysregulation of REV-ERBα impairs GABAergic function and promotes epileptic seizures in preclinical models
Rev-erbα is a known regulator of the circadian clock. Here, the authors show that Rev-erbα is also a regulator of synaptic dysfunction in preclinical models of epilepsy.
- Tianpeng Zhang
- , Fangjun Yu
- & Baojian Wu
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Article
| Open AccessOverexpression of neuregulin 1 in GABAergic interneurons results in reversible cortical disinhibition
The molecular and cellular mechanisms of cortical disinhibition as a common feature of many psychiatric diseases are not fully understood. The authors identify an interaction between NRG1 and Nav1.1 sodium channel as a mechanism of how NRG1 modulates the excitability of GABAergic interneurons.
- Yao-Yi Wang
- , Bing Zhao
- & Dong-Min Yin
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Article
| Open AccessTranscriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus
The relationship between gene expression and morphology to classify PV interneurons is unclear. Here, the authors show transcriptional continuity of morphologically distinct mouse hippocampal PV interneurons subtypes, combining single-cell RNA sequencing and electrophysiology.
- Lin Que
- , David Lukacsovich
- & Csaba Földy
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Article
| Open AccessAstrocytic pyruvate dehydrogenase kinase-2 is involved in hypothalamic inflammation in mouse models of diabetes
Hypothalamic inflammation is involved in the pathogenesis of diabetes. The underlying mechanisms are unclear. Here, the authors show that astrocytic PDK2 ablation or inhibition attenuates hypothalamic inflammation in mouse models of diabetes.
- Md Habibur Rahman
- , Anup Bhusal
- & Kyoungho Suk
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Article
| Open AccessDefective minor spliceosomes induce SMA-associated phenotypes through sensitive intron-containing neural genes in Drosophila
Spinal muscular atrophy (SMA) is associated with minor splicing-related defects. Here the authors develop Drosophila models with minor spliceosomal-snRNA deletions, and demonstrate SMA-like phenotypes.
- Liang Li
- , Zhan Ding
- & Yong-Zhen Xu
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Article
| Open AccessSystematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow
Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.
- Vartika Mishra
- , Diane B. Re
- & Serge Przedborski
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Article
| Open AccessOpen syntaxin overcomes exocytosis defects of diverse mutants in C. elegans
Opening of the UNC-64/syntaxin closed conformation by UNC-13/Munc13 to form the neuronal SNARE complex is critical for neurotransmitter release. Here the authors show that facilitating the opening of syntaxin enhances exocytosis not only in unc-13 nulls as well as in diverse C. elegans mutants.
- Chi-Wei Tien
- , Bin Yu
- & Shuzo Sugita
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Article
| Open AccessAn HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline
HDAC6 is a tau deacetylase and acetylation of tau inhibits its function and promotes aggregation. Here the authors show that HDAC6 protects against tau accumulation in a mouse model of tauopathy.
- Hanna Trzeciakiewicz
- , Deepa Ajit
- & Todd J. Cohen
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Article
| Open AccessSynaptic vesicle traffic is supported by transient actin filaments and regulated by PKA and NO
Transport of membrane proteins within the cell is thought to mainly rely on microtubule-based transport, but the role of microtubules in neuronal cell recycling of synaptic vesicles is unclear. Here, the authors show that axonal movement of recycling vesicles may be driven not by microtubules but primarily by actin polymerization.
- Nicolas Chenouard
- , Feng Xuan
- & Richard W. Tsien
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Article
| Open AccessGenome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning
Fear and fear extinction learning are dynamic. These dynamic changes are underlined by transcriptional changes. Here, the authors translationally profiled Crh neurons in the amygdala and and identified relevant gene networks.
- Kenneth M. McCullough
- , Chris Chatzinakos
- & Kerry J. Ressler
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Article
| Open AccessSynapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer
Mossy fiber synapses are key in CA3 microcircuit function. Here, the authors profile the mossy fiber synapse proteome and cell-surface interactome. They uncover a diverse repertoire of cell-surface proteins and identify the receptor IgSF8 as a regulator of CA3 microcircuit connectivity and function.
- Nuno Apóstolo
- , Samuel N. Smukowski
- & Joris de Wit
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Article
| Open AccessIdentification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
The pathophysiology of epilepsy is unclear. Here, the authors present single-nuclei transcriptomic profiling of human temporal lobe epilepsy from patients. They identified epilepsy-associated neuronal subtypes, and a panel of dysregulated genes, predicting neuronal circuits contributing to epilepsy.
- Ulrich Pfisterer
- , Viktor Petukhov
- & Konstantin Khodosevich
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Article
| Open AccessSatellite glial cells promote regenerative growth in sensory neurons
The contribution of satellite glia to peripheral nerve regeneration is unclear. Here, the authors show that satellite glia are transcriptionally distinct from Schwann cells, share similarities with astrocytes, and, upon injury, they contribute to axon regeneration via Fasn-PPARα signalling pathway.
- Oshri Avraham
- , Pan-Yue Deng
- & Valeria Cavalli
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Article
| Open AccessCircuit-specific hippocampal ΔFosB underlies resilience to stress-induced social avoidance
Chronic stress is a risk factor for mood disorders, yet the molecular and circuit mechanisms of stress-induced changes are not well understood. Here, the authors report the role of the transcription factor ΔFosB in driving activity changes in response to stress in glutamatergic neurons in the ventral hippocampus that project to nucleus accumben.
- Andrew L. Eagle
- , Claire E. Manning
- & Alfred J. Robison
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Article
| Open AccessABHD4-dependent developmental anoikis safeguards the embryonic brain
During embryonic development, neural progenitor cells undergo numerous cell divisions. Here, the authors show that ABHD4-mediated developmental anoikis distinguishes the physiological delamination and the pathological detachment of progenitor cells with relevance to fetal alcohol-induced apoptosis.
- Zsófia I. László
- , Zsolt Lele
- & István Katona
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Article
| Open AccessRNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.
- Mauro Montalbano
- , Salome McAllen
- & Rakez Kayed
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Article
| Open AccessNeuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry
Neuroligins are postsynaptic cell adhesion molecules that are involved in synapse function and autism spectrum disorder. The authors show that NLG2-mediated GABAergic transmission at the thalamic reticular nucleus-thalamic circuit is a common mechanism underlying epileptic seizures and ASD.
- Feng Cao
- , Jackie J. Liu
- & Zhengping Jia
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Article
| Open AccessTranscriptomic and cellular decoding of regional brain vulnerability to neurogenetic disorders
How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.
- Jakob Seidlitz
- , Ajay Nadig
- & Armin Raznahan
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Article
| Open AccessLiquid-liquid phase separation induces pathogenic tau conformations in vitro
Tau plays an important role in tauopathies and undergoes liquid-liquid phase separation (LLPS). The authors show that disease-related P301L mutant and phosphomimic (S199E/S202E/T205E) tau enhance LLPS in vitro at physiological levels, and using specific antibodies, that tau LLPS leads to pathological conformations such as N-terminal exposure and oligomeric species.
- Nicholas M. Kanaan
- , Chelsey Hamel
- & Benjamin Combs
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Article
| Open AccessThe netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors
The netrin receptor UNC-40/DCC is required to recruit GABAAR at neuromuscular junctions in C. elegans. Here, the authors show that UNC-40/DCC assembles an intracellular synaptic scaffold, regulating the content of GABAAR and inhibitory neurotransmission.
- Xin Zhou
- , Marine Gueydan
- & Jean-Louis Bessereau
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Article
| Open AccessTruncation of mutant huntingtin in knock-in mice demonstrates exon1 huntingtin is a key pathogenic form
The mechanisms by which mutant Huntington protein Htt leads to selective neurodegeneration are not fully understood. Here, using gene editing in HD140Q knock-in mice, the authors show that exon1 Htt is a critical pathological form of the protein.
- Huiming Yang
- , Su Yang
- & Xiao-Jiang Li
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Article
| Open AccessPTSD is associated with neuroimmune suppression: evidence from PET imaging and postmortem transcriptomic studies
Neuroinflammation has been proposed to accompany the peripheral inflammation observed in PTSD. Here, authors find lower in vivo and postmortem levels of neuroimmune marker TSPO (translocator protein) in PTSD, in association with greater PTSD severity and higher plasma CRP.
- Shivani Bhatt
- , Ansel T. Hillmer
- & Kelly P. Cosgrove
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Article
| Open AccessMALT-1 mediates IL-17 neural signaling to regulate C. elegans behavior, immunity and longevity
IL-17 is a pro-inflammatory molecule that can also regulate neural circuit function. Here the authors use C. elegans to show that the paracaspase MALT-1 lies downstream of IL-17 signaling and regulates many aspects of C. elegans biology, including escape behavior, associative learning, immunity and longevity.
- Sean M. Flynn
- , Changchun Chen
- & Mario de Bono
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Article
| Open AccessFunctional and molecular heterogeneity of D2R neurons along dorsal ventral axis in the striatum
Striatal dopaminoceptive neurons are molecularly and functionally heterogeneous. Here, the authors provide the translatome of D2R striatal neurons and identified hundreds of region specific molecular markers as well as testing their resource to shed light into function.
- Emma Puighermanal
- , Laia Castell
- & Emmanuel Valjent
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Article
| Open AccessElevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations
The main cell types involved in autism spectrum disorders through elevated protein synthesis are not well identified. Here, the authors show that overexpression of translation initiation factor eIF4E in microglia results in autism-like behaviour in male, but not female, mice.
- Zhi-Xiang Xu
- , Gyu Hyun Kim
- & Baoji Xu
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Article
| Open AccessTrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits
The TrkB receptor is known to regulate obesity via appetite control, but the underlying neural circuits are not known. Here, the authors show that selective modulation of TrkB+ neurons in the paraventricular hypothalamus regulates food intake via circuits to ventromedial hypothalamus and lateral parabrachial nucleus.
- Juan Ji An
- , Clint E. Kinney
- & Baoji Xu
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Article
| Open AccessThe mechanism of a high-affinity allosteric inhibitor of the serotonin transporter
The serotonin transporter (SERT) terminates serotonin signaling and its activity is modulated by antidepressants. Here authors reveal the mechanistic details underlying the coupling between the two binding sites in SERT and a high-affinity ligand for the allosteric site.
- Per Plenge
- , Ara M. Abramyan
- & Claus J. Loland
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Article
| Open AccessEndophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin
Endophilins-A are conserved membrane-associated proteins required for endocytosis. Here, the authors report that endophilins-A also promote exocytosis of neurosecretory vesicles by coordinating priming and fusion through intersectin-1, independently of their roles in different types of endocytosis.
- Sindhuja Gowrisankaran
- , Sébastien Houy
- & Ira Milosevic
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Article
| Open AccessIdentification of region-specific astrocyte subtypes at single cell resolution
Astrocytes are a major cell type in the central nervous system. Using single cell transcriptome sequencing, the authors identify multiple astrocyte subtypes in the adult mouse CNS, which map to distinct spatial locations and show correlations to cell morphology and physiology.
- Mykhailo Y. Batiuk
- , Araks Martirosyan
- & Matthew G. Holt
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Article
| Open AccessTranscriptomic evidence that von Economo neurons are regionally specialized extratelencephalic-projecting excitatory neurons
Little is known about von Economo neurons, which have been described in a subset of mammals and appear to be selectively lost in several human neurological diseases. Here, authors reveal the gene expression profile of these cells and show that they are likely long-distance projection neurons.
- Rebecca D. Hodge
- , Jeremy A. Miller
- & Ed S. Lein
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Article
| Open AccessHyperactivated PTP1B phosphatase in parvalbumin neurons alters anterior cingulate inhibitory circuits and induces autism-like behaviors
LMO4 has been linked genetically to autism spectrum disorder and intellectual disability. Here, the authors investigate a role of LMO4 in parvalbumin neurons and, specifically, the regulation of dorsal ACC inhibitory circuits.
- Li Zhang
- , Zhaohong Qin
- & Hsiao-Huei Chen