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| Open AccessCoordination chemogenetics for activation of GPCR-type glutamate receptors in brain tissue
Cell-type-specific activation of receptors is desirable for elucidating their roles in tissues or animals. Here, the authors developed a chemogenetic method for direct activation of mGlu1, a GPCR-type glutamate receptor subtype, and demonstrate its use in mouse brain tissue.
- Kento Ojima
- , Wataru Kakegawa
- & Shigeki Kiyonaka
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Article
| Open AccessMafa-dependent GABAergic activity promotes mouse neonatal apneas
Apneas are associated with many pathological conditions. Here, the authors show in a mouse model that stabilization of the transcription factor Mafa in brainstem GABAergic neurons may contribute to apnea, by decreasing motor drive to muscles controlling the airways.
- Laure Lecoin
- , Bowen Dempsey
- & Jean Champagnat
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Article
| Open AccessInduction of synapse formation by de novo neurotransmitter synthesis
Neuronal communication relies on matching different neurostransmitter types with their appropriate receptors. The authors here demonstrate that release of a novel neurotransmitter from presynaptic terminals can induce both the accumulation and activation of its corresponding receptors on postsynaptic neurons.
- Scott R. Burlingham
- , Nicole F. Wong
- & Soham Chanda
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Article
| Open AccessMolecular encoding and synaptic decoding of context during salt chemotaxis in C. elegans
The nematode C. elegans moves around to find an optimal environment. This work demonstrates how it can detect and move towards a previously learned salinity using the salt-sensing neuron ASER.
- Shingo Hiroki
- , Hikari Yoshitane
- & Yuichi Iino
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Article
| Open AccessCell type-specific biotin labeling in vivo resolves regional neuronal and astrocyte proteomic differences in mouse brain
Current isolation-based approaches for cell type-specific proteomics pose several challenges. Here, the authors present an approach for in vivo cell type-specific protein labeling to characterize proteomic differences between neurons and astrocytes in their native state in adult mouse brain.
- Sruti Rayaprolu
- , Sara Bitarafan
- & Srikant Rangaraju
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Article
| Open AccessRNP components condense into repressive RNP granules in the aging brain
Aberrant RNA condensates are a hallmark of age-related neurodegenerative diseases. Here, the authors show that RNA condensation increases in aging Drosophila brains, triggering translation repression.
- Kavya Vinayan Pushpalatha
- , Mathilde Solyga
- & Florence Besse
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Article
| Open AccessRNA supply drives physiological granule assembly in neurons
RNA granules are important regulators of RNA metabolism. Here the authors report that RNA granules containing RNA helicase DDX6 disassemble during neuronal maturation.
- Karl E. Bauer
- , Niklas Bargenda
- & Michael A. Kiebler
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Article
| Open AccessTeneurins assemble into presynaptic nanoclusters that promote synapse formation via postsynaptic non-teneurin ligands
Teneurins are cell-adhesion molecules that help form synaptic connections between neurons. Here the authors demonstrate that teneurins on the presynaptic side are essential to form connections.
- Xuchen Zhang
- , Pei-Yi Lin
- & Thomas C. Südhof
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Article
| Open AccessChromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia
Schizophrenia (SZ) is a severe psychiatric disorder; unfortunately, only ~1/3 of patients respond favorably to treatment. Here, the authors reveal hyperacetylation of histone H2A.Z in SZ neurons and postmortem SZ human brain tissues. They further show BRD4 is a reader of hyperacetylated H2A.Z and treatment with bromodomain inhibitor JQ1 largely rescues abnormal gene expression associated with SZ.
- Lorna A. Farrelly
- , Shuangping Zheng
- & Ian Maze
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Article
| Open AccessMultiomic profiling of the acute stress response in the mouse hippocampus
Acute stress can help individuals to respond to challenging events, although chronic stress leads to maladaptive changes. Here, the authors present a multi omic analysis profiling acute stress-induced changes in the mouse hippocampus, providing a resource for the scientific community.
- Lukas M. von Ziegler
- , Amalia Floriou-Servou
- & Johannes Bohacek
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Article
| Open AccessSWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress
Repeated exposure to social stressors in rodents results in behavioural changes. Here the authors show that behavioural adaptations to stress are associated with nuclear organization changes through SWI/SNF chromatin remodeler in specific neuronal populations of the mesolimbic system.
- Abdallah Zayed
- , Camille Baranowski
- & Sébastien Parnaudeau
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Article
| Open AccessMaintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor
Mitochondrial dysfunction in dopaminergic neurons is a pathological hallmark of Parkinson’s disease. Here, the authors find a conserved mechanism by which a single transcription factor controls mitochondrial health in dopaminergic neurons during the aging process.
- Federico Miozzo
- , Eva P. Valencia-Alarcón
- & Emi Nagoshi
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Article
| Open AccessChanges to gut amino acid transporters and microbiome associated with increased E/I ratio in Chd8+/− mouse model of ASD-like behavior
The gut microbiota has been shown to modulate the neural function via the microbiota-gut-brain axis. Here, the authors show that Bacteroides uniformis, a gut commensal bacterium, restores the ASD-like phenotypes by reducing intestinal amino acid transport in an ASD mouse model.
- You Yu
- , Bing Zhang
- & Fangqing Zhao
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Article
| Open AccessThe insect somatostatin pathway gates vitellogenesis progression during reproductive maturation and the post-mating response
In mammals, somatostatin plays a role in preventing the release of sex hormones before puberty begins. A Drosophila study uncovered the process by which insect somatostatin controls ovarian development in response to developmental and mating signals.
- Chen Zhang
- , Anmo J. Kim
- & Young-Joon Kim
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Article
| Open AccessOrganic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice
Chronic pain is sustained by alterations in gene transcription. Here, the authors show that increased expression of Organic Anionic Transporter 1 in the spinal cord is epigenetically controlled and key to hypersensitivity in pathological pain.
- Christian Litke
- , Anna M. Hagenston
- & Daniela Mauceri
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Article
| Open AccessSchizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats
The effects of SAP97 mutations associated with schizophrenia on synaptic function are unclear. Here, the authors show that schizophrenia-related SAP97 mutations enhance glutamatergic synapse strength in the dentate gyrus, impairing contextual episodic memory in rats.
- Yuni Kay
- , Linda Tsan
- & Bruce E. Herring
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Article
| Open AccessAmylin-Calcitonin receptor signaling in the medial preoptic area mediates affiliative social behaviors in female mice
The mechanisms coordinating the sensing and seeking of social contacts are unclear. Here, the authors show that amylin-calcitonin receptor signalling in the media preoptic area mediates affiliative social behaviors in female mice.
- Kansai Fukumitsu
- , Misato Kaneko
- & Kumi O. Kuroda
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Article
| Open AccessHemoglobin in the blood acts as a chemosensory signal via the mouse vomeronasal system
The vomeronasal system regulates sensing of various environmental cues. Here, the authors show that exposure to hemoglobin results in the activation of Vmn2r88+ vomeronasal sensory neurons in both male and female mice. However, exposure to hemoglobin enhances digging and rearing behaviour in lactating female mice only.
- Takuya Osakada
- , Takayuki Abe
- & Kazushige Touhara
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Article
| Open AccessAberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis
CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage disease typically with childhood onset of neurodegenerative symptoms. Here the authors report that in a mouse model of CLN7 disease neuronal reactive oxygen species and the activity of glycolytic enzyme PFKFB3 are increased, while PFKFB3 inhibition ameliorates hallmarks of pathology.
- Irene Lopez-Fabuel
- , Marina Garcia-Macia
- & Juan P. Bolaños
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Article
| Open AccessFocused ultrasound excites cortical neurons via mechanosensitive calcium accumulation and ion channel amplification
The mechanisms underlying the effects of ultrasonic modulation of neural activity are unclear. Here, the authors show that focused ultrasound excites cultured primary murine cortical neurons via calcium accumulation through specific mechanosensitive ion channels.
- Sangjin Yoo
- , David R. Mittelstein
- & Mikhail G. Shapiro
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Article
| Open AccessMammalian brain glycoproteins exhibit diminished glycan complexity compared to other tissues
Protein glycosylation is critical in brain development and disease. Here, the authors characterize brain glycans in detail, showing that they are simpler and more homogenous than glycans from other tissues and providing a basis for future studies of brain glycosylation.
- Sarah E. Williams
- , Maxence Noel
- & Robert G. Mealer
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Article
| Open AccessDeterminants of synapse diversity revealed by super-resolution quantal transmission and active zone imaging
Super-resolution quantal imaging relates transmission at excitatory synapses to presynaptic molecular composition. The authors find that evoked transmission varies greatly between synapses and is uncorrelated and physically separate from spontaneous transmission, and identify responsible presynaptic proteins.
- Zachary L. Newman
- , Dariya Bakshinskaya
- & Ehud Y. Isacoff
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Article
| Open AccessStructural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation
Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the synthesis of the catecholamine neurotransmitters and hormones dopamine (DA), adrenaline and noradrenaline. Here, the authors present the cryo-EM structures of full-length human TH in the apo form and bound with DA, as well as the structure of Ser40 phosphorylated TH, and discuss the inhibitory and stabilizing effects of DA on TH and its counteraction by Ser40-phosphorylation.
- María Teresa Bueno-Carrasco
- , Jorge Cuéllar
- & José M. Valpuesta
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Article
| Open AccessReactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.
- Zoeb Jiwaji
- , Sachin S. Tiwari
- & Giles E. Hardingham
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Article
| Open AccessGPCR voltage dependence controls neuronal plasticity and behavior
G-protein coupled receptors are regulated by the membrane potential in vitro. Here, the authors show that muscarinic receptor voltage independence causes a strong behavioural effect of increased odour habituation, showing that these receptors are also in vivo modulated by the membrane potential.
- Eyal Rozenfeld
- , Merav Tauber
- & Moshe Parnas
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Article
| Open AccessNeuron-specific chromosomal megadomain organization is adaptive to recent retrotransposon expansions
Repeat-rich sequences play a role in 3D genome architecture in higher eukaryotes; however, this remains unexplored in brain cells. Here, the authors show that upregulation of endogenous retroviral (ERV) sequences is linked to changes in the 3D structure in the brain, which is also observed by comparison of mouse strains with recent retrotransposon expansion.
- Sandhya Chandrasekaran
- , Sergio Espeso-Gil
- & Schahram Akbarian
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Article
| Open AccessExtracellular matrix remodeling through endocytosis and resurfacing of Tenascin-R
Synapses are surrounded by an extracellular matrix (ECM) of extremely long-lived proteins that is thought to only be remodeled by proteolysis and de novo synthesis. Here, the authors show an alternative molecular recycling mechanism that occurs for the key ECM protein Tenascin-R.
- Tal M. Dankovich
- , Rahul Kaushik
- & Silvio O. Rizzoli
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Article
| Open AccessAn injury-induced serotonergic neuron subpopulation contributes to axon regrowth and function restoration after spinal cord injury in zebrafish
The mechanisms involved in regeneration of the spinal cord after injury are unclear. Here, the authors show that a subpopulation of intraspinal serotonergic neurons localized at the injury site stimulates axonal regrowth of interneurons via 5-HT1B receptor, resulting in recovery of function following SCI in zebrafish.
- Chun-Xiao Huang
- , Yacong Zhao
- & Jianren Song
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Article
| Open AccessAtlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue
Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer’s disease human brain tissue resulting in changes at protein level.
- Yiyi Ma
- , Eric B. Dammer
- & Philip L. De Jager
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Article
| Open AccessFat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice
Post-transcriptional modification of RNA can contribute to regulating behavior. Here, the authors show that modulating the expression of Fto results in epitranscriptomic changes in the mouse hippocampus associated with depression-like behavior.
- Shu Liu
- , Jianbo Xiu
- & Qi Xu
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Article
| Open AccessStructures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca2+-dependent switch from intra- to intermembrane dimerization
Tweety Homologs (TTYHs) are highly conserved membrane proteins, whose functions remain poorly understood. Here, the authors present the cryo-EM structures of murine TTYH2 and TTYH3 that form cis-dimers in the presence of Ca2+, whereas in the absence of Ca2+ TTYH2 adopts monomeric and trans-dimeric structures. The presented structures lack ion conducting pathways, which is consistent with results from electrophysiology measurements.
- Baobin Li
- , Christopher M. Hoel
- & Stephen G. Brohawn
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Article
| Open AccessIdentification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis
UBE3A gene dysregulation is associated with neurodevelopmental disorders, but predicting the function of UBE3A variants remains difficult. The authors use a high-throughput assay to categorize variants by functional activity, and show that UBE3A hyperactivity increases the risk of neurodevelopmental disease.
- Kellan P. Weston
- , Xiaoyi Gao
- & Jason J. Yi
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Article
| Open AccessRepeated exposure with short-term behavioral stress resolves pre-existing stress-induced depressive-like behavior in mice
Chronic stress induces maladaptive changes in the neural networks and it’s associated with mood disorders. Here, the authors show that repeated exposure to short-term stress can resolve pre-existing chronic stress induced depressive-like behaviour in mice.
- Eun-Hwa Lee
- , Jin-Young Park
- & Pyung-Lim Han
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Article
| Open AccessPharmacoSTORM nanoscale pharmacology reveals cariprazine binding on Islands of Calleja granule cells
The authors introduce PharmacoSTORM single-molecule imaging that uses fluorescent ligands and immunolabeling for cellular and subcellular nanoscale molecular pharmacology. They demonstrate its capabilities by visualizing cariprazine binding to D3 dopamine receptors on Islands of Calleja granule cell axons.
- Susanne Prokop
- , Péter Ábrányi-Balogh
- & István Katona
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Article
| Open AccessDopamine D2 receptor regulates cortical synaptic pruning in rodents
Synaptic pruning is important during development and synaptic plasticity. Here, the authors show that the dopamine D2 receptor (Drd2) in the anterior cingulate cortex regulates synaptic pruning, affecting LTD and behaviour in transgenic rats.
- Ya-Qiang Zhang
- , Wei-Peng Lin
- & Dong-Min Yin
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Article
| Open AccessMicroglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Whether microglial activation constitutes a primary pathological event in synucleinopathies is not known. Here, the authors generated a mouse model over-expressing α-synuclein in microglial cells and found these mice developed progressive dopaminergic neuron degeneration and microglia developed a reactive, pro-inflammatory state with phagocytic exhaustion.
- Simone Bido
- , Sharon Muggeo
- & Vania Broccoli
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Article
| Open AccessNeuronal ribosomes exhibit dynamic and context-dependent exchange of ribosomal proteins
Ribosomes, assembled in the nucleus and perinuclear region, are thought to remain invariant throughout their lifetime. Here the authors document the dynamic association or exchange of ribosomal proteins within mature ribosomes of neuronal cells.
- Claudia M. Fusco
- , Kristina Desch
- & Erin M. Schuman
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Article
| Open AccessA C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation
A hexanucleotide repeat expansion of C9orf72 is translated to dipeptide repeat proteins in amyotrophic lateral sclerosis and frontotemporal dementia patients. Here the authors generate a C. elegans model of C9orf72-mediated ALS/FTD and show that translation initiation factor eIF2D regulates the dipeptide repeat protein expression.
- Yoshifumi Sonobe
- , Jihad Aburas
- & Paschalis Kratsios
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Article
| Open AccessATP-citrate lyase promotes axonal transport across species
Microtubule tracks are important for the transport of molecules within axons. Here, the authors show that ATAT1, the enzyme responsible for acetylating a-tubulin, receives acetyl groups from ATP citrate lyase whose stability is regulated by Elongator, a protein mutated in the neuronal disease Familial dysautonomia.
- Aviel Even
- , Giovanni Morelli
- & Laurent Nguyen
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Article
| Open AccessNeurofibromin 1 in mushroom body neurons mediates circadian wake drive through activating cAMP–PKA signaling
The molecular mechanism by which clock neurons transmit timing information to non-clock neurons is poorly understood. Here, the authors show that circadian clocks drive rhythmic expression of hundreds of genes in mushroom body neurons and drive calcium rhythms via NF1-cAMP/PKAC1 signalling in Drosophila.
- Pedro Machado Almeida
- , Blanca Lago Solis
- & Emi Nagoshi
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Article
| Open AccessNG2 glia-derived GABA release tunes inhibitory synapses and contributes to stress-induced anxiety
Nerve/glial antigen 2 (NG2) glia can sense synaptic inputs from neurons. Here, the authors show NG2 glia form functional GABAergic synapses by regulating inhibitory synaptic transmission onto adjacent hippocampal interneurons, and activation of NG2 glia induces anxiety-like behaviour in a mouse model of chronic social defeat stress.
- Xiao Zhang
- , Yao Liu
- & Xiaoping Tong
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Article
| Open AccessA harmonized atlas of mouse spinal cord cell types and their spatial organization
Single-cell profiling has led to the identification of diverse cell types. Here, the authors generate a harmonized cell atlas of the mouse post-natal spinal cord. They also provide spatial analysis of the distribution of the identified cell types and an open-source cell type classifier.
- Daniel E. Russ
- , Ryan B. Patterson Cross
- & Ariel J. Levine
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Article
| Open AccessAllosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state
Here, the authors use smFRET to assess the structural dynamics of metabotropic glutamate receptor mGlu2 and show that a positive allosteric modulator or the Gi protein stabilize mGlu2 in the glutamate-induced active state, leading to the full activation of the receptor.
- Anne-Marinette Cao
- , Robert B. Quast
- & Emmanuel Margeat
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Article
| Open AccessSelective targeting of the TLR2/MyD88/NF-κB pathway reduces α-synuclein spreading in vitro and in vivo
The mechanisms underlying the spreading of α-synuclein in various α-synucleinopathies are unclear. Here, the authors show that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading, reduce neuroinflammation, and protect dopaminergic neurons in vitro and in mouse models
- Debashis Dutta
- , Malabendu Jana
- & Kalipada Pahan
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Article
| Open AccessSmall-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Mitochondrial dysfunction is a common hallmark of neurological disorders. Here, the authors identify CHIR99021 as a potent enhancer of mitochondrial function, which improved mitochondrial phenotypes in Huntington’s disease models. CHIR99021 was shown to stabilize calpastatin, which suppressed calpain activation and Drp1-induced mitochondrial fragmentation.
- Di Hu
- , Xiaoyan Sun
- & Xin Qi
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Article
| Open AccessCapillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling in mice
Microglia are involved in debris clearance and synaptic pruning, among other processes. However, their direct interaction with the brain vasculature is less clear. Here, the authors show that capillary-associated microglia (CAMs) regulate vascular tone via PANX1-P2RY12 signalling.
- Kanchan Bisht
- , Kenneth A. Okojie
- & Ukpong B. Eyo
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Article
| Open AccessOlfactory bulb astrocytes mediate sensory circuit processing through Sox9 in the mouse brain
Astrocytes can regulate neuronal activity. Here, the authors show that astrocyte-specific deletion of Sox9 results in impaired neuronal sensory processing in the mouse adult olfactory bulb.
- Kevin Ung
- , Teng-Wei Huang
- & Benjamin R. Arenkiel
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Article
| Open AccessAMPA receptor anchoring at CA1 synapses is determined by N-terminal domain and TARP γ8 interactions
Changes in AMPAR localization can control the strength of synaptic transmission. Here, the authors show that the interactions of TARP γ8 and the AMPAR N-terminal domain work together to regulate receptor accumulation and positioning at the post-synapse of mouse hippocampal CA1 neurons.
- Jake F. Watson
- , Alexandra Pinggera
- & Ingo H. Greger
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Article
| Open AccessNeuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior
The link between tRNA modifications, protein translation, and behavior is unclear. Here, the authors show that neuronal Nsun2 deficiency results in codon-specific epitranscriptomic changes of Gly-tRNAs and proteomic changes affecting synaptic signaling and behavior in mice.
- J. Blaze
- , A. Navickas
- & S. Akbarian