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Molecular and Cellular Neurosciences

Hajime Shiotani, Muneaki Miyata, Kiyohito Mizutani, Shujie Wang, Akira Mizoguchi, Hideki Mochizuki, Kenji Mandai, Yoshimi Takai
The medial habenula (MHb) receives septal inputs and sends efferents to the interpeduncular nucleus and is implicated in stress, depression, memory, and nicotine withdrawal syndrome. We previously showed by immunofluorescence microscopy that the cell adhesion molecule nectin-2α is expressed in the cholinergic neurons in the developing and adult mouse MHbs and localized at the boundary between the adjacent somata of clustered cholinergic neurons where the voltage-gated A-type K+ channel Kv4.2 is localized. We further showed by immunoelectron microscopy that Kv4...
November 5, 2018: Molecular and Cellular Neurosciences
Wanda M Snow, Kensuke Oikawa, Jelena Djordjevic, Benedict C Albensi
In Alzheimer's disease (AD), characterized by cognitive deterioration, synaptic alterations are frequently reported. The TgCRND8 model, in which mice develop AD-like amyloid β plaque formation, has been used to investigate the effects of amyloidosis on synaptic function. Background strain impacts the behavioral and neuropathological phenotype of mice in this model, but whether this extends to synaptic function is unknown. We investigated the influence of background strain on basal synaptic transmission and long-term potentiation (LTP) in the hippocampus of TgCRND8 mice (13-16 months) on hybrid backgrounds of (129SvEv/Tac) x (C3H/C57/129SvEv/Tac) (aka "129") or (C57) x (C3H/C57) (aka "C3H")...
November 4, 2018: Molecular and Cellular Neurosciences
Petra Steinacker, Peggy Barschke, Markus Otto
The discovery that aggregated transactive response DNA-binding protein 43 kDa (TDP-43) is the major component of pathological ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) caused seminal progress in the unveiling of the genetic bases and molecular characteristics of these now so-called TDP-43 proteinopathies. Substantial increase in the knowledge of clinic-pathological coherencies, especially for FTLD variants, could be made in the last decade, but also revealed a considerable complexity of TDP-43 pathology and often a poor correlation of clinical and molecular disease characteristics...
November 3, 2018: Molecular and Cellular Neurosciences
Mayara Vieira Mundim, Laura Nicoleti Zamproni, Agnes Araújo Sardinha Pinto, Layla Testa Galindo, André Machado Xavier, Isaias Glezer, Marimélia Porcionatto
Traumatic brain injury is an important cause of global morbidity and mortality. After an initial injury, there is a cascade of cellular and molecular events that ultimately lead to cell death. Therapies aim to both counteract these mechanisms and replenish the lost cell population in order to improve recovery. The adult mammal brain has at least two neurogenic regions that maintain physiological functions: the subgranular zone of the dentate gyrus in the hippocampus, which produces neurons that integrate locally, and the subventricular zone (SVZ) adjacent to the lateral ventricles, which produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulbs...
October 31, 2018: Molecular and Cellular Neurosciences
Takahiro Seki, Masahiro Sato, Ayumu Konno, Hirokazu Hirai, Yuki Kurauchi, Akinori Hisatsune, Hiroshi Katsuki
Hydrogen sulfide and reactive sulfur species are regulators of physiological functions, have antioxidant effects against oxidative stresses, and are endogenously generated from l-cysteine. Recently, a novel pathway that generates hydrogen sulfide and reactive sulfur species from d-cysteine has been identified. d-Amino acid oxidase (DAO) is involved in this pathway and, among the various brain regions, is especially abundant in the cerebellum. d-Cysteine has been found to be a better substrate in the generation of hydrogen sulfide in the cerebellum than l-cysteine...
October 19, 2018: Molecular and Cellular Neurosciences
Maria Hersom, Charlotte Goldeman, Natasia Pretzer, Birger Brodin
BACKGROUND: The genes encoding β-actin and GAPDH are two of the most commonly used reference genes for normalization in in vitro blood-brain barrier studies. Studies have, however, shown that these reference genes might not always be the best choice. The aim of the present study was to evaluate 10 reference genes for use in mRNA profiling studies in primary cultures of brain endothelial cells of bovine origin. METHODS: Gene evaluations were performed by qPCR in mono-culture and in co-cultures with astrocytes...
October 10, 2018: Molecular and Cellular Neurosciences
Anna Ansell-Schultz, Juan F Reyes, My Samuelsson, Martin Hallbeck
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oAβ) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oAβ, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells...
September 23, 2018: Molecular and Cellular Neurosciences
Nora E Gray, Jonathan A Zweig, Maya Caruso, Jennifer Y Zhu, Kirsten M Wright, Joseph F Quinn, Amala Soumyanath
Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation...
September 22, 2018: Molecular and Cellular Neurosciences
Annie Vu, Tyler Humphries, Sean Vogel, Adam Haberman
Expansions of polygutamine-encoding stretches in several genes cause neurodegenerative disorders including Huntington's Disease and Spinocerebellar Ataxia type 3. Expression of the human disease alleles in Drosophila melanogaster neurons recapitulates cellular features of these disorders, and has therefore been used to model the cell biology of these diseases. Here, we show that polyglutamine disease alleles expressed in Drosophila photoreceptors disrupt actin structure at rhabdomeres, as other groups have shown they do in Drosophila and mammalian dendrites...
August 24, 2018: Molecular and Cellular Neurosciences
Tomoyuki Ueda, Masatoshi Inden, Yuta Asaka, Yuji Masaki, Hisaka Kurita, Wakako Tanaka, Eiji Yamaguchi, Akichika Itoh, Isao Hozumi
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis, and death. Although its neuropathology is well investigated, currently, effective treatments are unavailable. The mechanism of ALS involves the aggregation and accumulation of several mutant proteins, including mutant copper‑zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) proteins. Previous reports have shown that excessive oxidative stress, associated with mitochondrial dysfunction and mutant protein accumulation, contributes to ALS pathology...
October 2018: Molecular and Cellular Neurosciences
Qian Zhang, Chengwu Li, Ting Zhang, Yaping Ge, Xiaojuan Han, Sifan Sun, Jianhua Ding, Ming Lu, Gang Hu
ATP-sensitive potassium (K-ATP) channels express in the central nervous system extensively which coupling cell metabolism and cellular electrical activity. K-ATP channels in mature substantia nigra (SN) dopaminergic (DA) neurons are composed of inwardly rectifying potassium channel (Kir) subunit 6.2 and sulfonylurea receptor 1 (SUR1). Our previous study revealed that regulating K-ATP channel exerts the protective effect on DA neurons in a mouse model of Parkinson's disease (PD). However, the detailed mechanism underlying the role of Kir6...
October 2018: Molecular and Cellular Neurosciences
Avery J Zucco, Valentina Dal Pozzo, Alina Afinogenova, Ronald P Hart, Orrin Devinsky, Gabriella D'Arcangelo
Tuberous Sclerosis Complex (TSC) is a disease caused by autosomal dominant mutations in the TSC1 or TSC2 genes, and is characterized by tumor susceptibility, brain lesions, seizures and behavioral impairments. The TSC1 and TSC2 genes encode proteins forming a complex (TSC), which is a major regulator and suppressor of mammalian target of rapamycin complex 1 (mTORC1), a signaling complex that promotes cell growth and proliferation. TSC1/2 loss of heterozygosity (LOH) and the subsequent complete loss of TSC regulatory activity in null cells causes mTORC1 dysregulation and TSC-associated brain lesions or other tissue tumors...
October 2018: Molecular and Cellular Neurosciences
Hannes Glaß, Arun Pal, Peter Reinhardt, Jared Sterneckert, Florian Wegner, Alexander Storch, Andreas Hermann
Mutations in the VPS13A gene leading to depletion of chorein protein are causative for Chorea Acanthocytosis (ChAc), a rare devastating disease, which is characterized by neurodegeneration mainly affecting the basal ganglia as well as deformation of erythrocytes. Studies on patient blood samples highlighted a dysregulation of Actin cytoskeleton caused by downregulation of the PI3K pathway and hyper-activation of Lyn-kinase, but to what extent these mechanisms are present and relevant in the affected neurons remains elusive...
October 2018: Molecular and Cellular Neurosciences
Matt C Danzi, Saloni T Mehta, Kireeti Dulla, Giulia Zunino, Daniel J Cooper, John L Bixby, Vance P Lemmon
Axon regeneration is a necessary step toward functional recovery after spinal cord injury. The AP-1 transcription factor c-Jun has long been known to play an important role in directing the transcriptional response of Dorsal Root Ganglion (DRG) neurons to peripheral axotomy that results in successful axon regeneration. Here we performed ChIPseq for Jun in mouse DRG neurons after a sciatic nerve crush or sham surgery in order to measure the changes in Jun's DNA binding in response to peripheral axotomy. We found that the majority of Jun's injury-responsive changes in DNA binding occur at putative enhancer elements, rather than proximal to transcription start sites...
October 2018: Molecular and Cellular Neurosciences
Philippe Ducharme, Juan G Zarruk, Samuel David, Joanne Paquin
Ceruloplasmin (Cp) is an important extracellular regulator of iron metabolism. We showed previously that it stimulates Reelin proteolytic processing and cell aggregation in cultures of developing neurons. Reelin is a secreted protein required for the correct positioning of neurons in the brain. It is cleaved in vivo into N-terminally-derived 300K and 180K fragments through incompletely known mechanisms. One of Reelin signaling targets is the actin-binding protein cofilin, the phosphorylation of which is diminished in Reelin-deficient mice...
October 2018: Molecular and Cellular Neurosciences
Daniel L Egbenya, Suleman Hussain, Yi-Chen Lai, Jun Xia, Anne E Anderson, Svend Davanger
Excitotoxicity caused by excessive stimulation of glutamate receptors, resulting in pathologically increased Ca2+ -concentrations, is a decisive factor in neurodegenerative diseases. We investigated long-term changes in synaptic contents of AMPA receptor subunits that play important roles in calcium regulation in chronic epilepsy. Such plastic changes may be either adaptive or detrimental. We used a kainic acid (KA)-based rat model of chronic temporal lobe epilepsy (TLE). Using hippocampal synaptosomes, we found significant reductions in the concentration of the AMPA receptor subunits GluA1 and GluA2, and the NMDA receptor subunit NR2B...
October 2018: Molecular and Cellular Neurosciences
Blanka R Szulc, Stephen T Hilton, Arnaud J Ruiz
We have synthesized a novel small molecule based on the pyrrolidinone-containing core structure of clausenamide, which is a candidate anti-dementia drug. The synthetic route yielded multi-gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor-mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l-glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices...
October 2018: Molecular and Cellular Neurosciences
Jacqueline E McDermott, Dena Goldblatt, Suzanne Paradis
To understand how proper circuit formation and function is established in the mammalian brain, it is necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synapse development. We previously demonstrated that the ligand-receptor pair, Sema4D and Plexin-B1, regulates inhibitory synapse development on an unprecedentedly fast time-scale while having no effect on excitatory synapse development. Here, we report previously undescribed synaptogenic roles for Sema4A and Plexin-B2 and provide new insight into Sema4D and Plexin-B1 regulation of synapse development in rodent hippocampus...
October 2018: Molecular and Cellular Neurosciences
Alina Monteagudo, Julianne Feola, Heather Natola, Changyi Ji, Christoph Pröschel, Gail V W Johnson
Astrocytes play an indispensable role in maintaining a healthy, functional neural network in the central nervous system (CNS). A primary function of CNS astrocytes is to support the survival and function of neurons. In response to injury, astrocytes take on a reactive phenotype, which alters their molecular functions. Reactive astrocytes have been reported to be both beneficial and harmful to the CNS recovery process subsequent to injury. Understanding the molecular processes and regulatory proteins that determine the extent to which an astrocyte hinders or supports neuronal survival is important within the context of CNS repair...
October 2018: Molecular and Cellular Neurosciences
Dan P Jackson, Jenhao H Ting, Paul D Pozniak, Claire Meurice, Stephanie S Schleidt, Anh Dao, Amy H Lee, Eva Klinman, Kelly L Jordan-Sciutto
E2F1 is a transcription factor classically known to regulate G0 /G1 to S phase progression in the cell cycle. In addition, E2F1 also regulates a wide range of apoptotic genes and thus has been well studied in the context of neuronal death and neurodegenerative diseases. However, its function and regulation in the mature central nervous system are not well understood. Alternative splicing is a well-conserved post-transcriptional mechanism common in cells of the CNS and is necessary to generate diverse functional modifications to RNA or protein products from genes...
October 2018: Molecular and Cellular Neurosciences
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