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1.
Nat Commun ; 10(1): 2431, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160566

RESUMO

Contextual modulation of neuronal responses by surrounding environments is a fundamental attribute of sensory processing. In the mammalian retina, responses of On-Off direction selective ganglion cells (DSGCs) are modulated by motion contexts. However, the underlying mechanisms are unknown. Here, we show that posterior-preferring DSGCs (pDSGCs) are sensitive to discontinuities of moving contours owing to contextually modulated cholinergic excitation from starburst amacrine cells (SACs). Using a combination of synapse-specific genetic manipulations, patch clamp electrophysiology and connectomic analysis, we identified distinct circuit motifs upstream of On and Off SACs that are required for the contextual modulation of pDSGC activity for bright and dark contrasts. Furthermore, our results reveal a class of wide-field amacrine cells (WACs) with straight, unbranching dendrites that function as "continuity detectors" of moving contours. Therefore, divergent circuit motifs in the On and Off pathways extend the information encoding of On-Off DSGCs beyond their direction selectivity during complex stimuli.


Assuntos
Acetilcolina/metabolismo , Células Amácrinas/metabolismo , Percepção de Movimento/fisiologia , Células Ganglionares da Retina/metabolismo , Sinapses/metabolismo , Visão Ocular/fisiologia , Ácido gama-Aminobutírico/metabolismo , Células Amácrinas/fisiologia , Animais , Conectoma , Dendritos/metabolismo , Ácido Glutâmico/metabolismo , Camundongos , Técnicas de Patch-Clamp , Receptores de GABA-A/genética , Células Ganglionares da Retina/fisiologia , Percepção Visual/fisiologia
2.
Life Sci ; 229: 187-199, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108095

RESUMO

Spinal cord injury (SCI) is a serious neurological disease without efficacious drugs. Anti-apoptosis and suppressing dendritic/synaptic degeneration in the anterior horn are essential targets after SCI. Previous studies found that hyperbaric oxygen therapy (HBOT) significantly protected rats after SCI. However, its potential effects and mechanisms remain unknown. The BDNF/TrkB signaling pathways evidently contribute to the SCI recovery. Currently, we mainly investigate the potential effects and mechanism of HBOT on anti-apoptosis and ameliorating impaired dendrites, dendritic spines and synapses after SCI. Establish SCI model and randomly divide rats into 5 groups. After SCI, rats were subjected to HBOT. ANA-12 is the specific inhibitor of BDNF/TrkB signal pathway. Changes in neurological deficit, neuronal morphology, apoptosis, protein expression and dendrite/synapse were examined by Basso-Beattie-Bresnahan (BBB) locomotor rating scale, Hematoxylin-eosin (HE) and Nissl staining, TUNEL staining, RT-PCR, Western blot, immunofluorescence and Golgi-Cox staining. We found HBOT suppressed dendritic/synaptic degeneration and alleviated apoptosis, consistent with the increase of BDNF and TrkB expression and improved neurological recovery. In contrast to the positive effects of HBOT, inhibitor increased degeneration and apoptosis. Moreover, we observed that these HBOT-mediated protective effects were significantly inhibited by inhibitor, consistent with the lower expression of BDNF/TrkB and worse neurobehavioral state. These findings suggest that hyperbaric oxygen therapy ameliorates spinal cord injury-induced neurological impairment by anti-apoptosis and suppressing dendritic/synaptic degeneration via upregulating the BDNF/TrkB signaling pathways.


Assuntos
Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/metabolismo , Oxigenação Hiperbárica/métodos , Degeneração Neural/prevenção & controle , Receptor trkB/metabolismo , Traumatismos da Medula Espinal/terapia , Sinapses/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor trkB/genética , Recuperação de Função Fisiológica , Transdução de Sinais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Sinapses/patologia
3.
Neurochem Res ; 44(6): 1387-1398, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31006092

RESUMO

The amyloid-degrading enzyme neprilysin (NEP) is one of the therapeutic targets in prevention and treatment of Alzheimer's disease (AD). As we have shown previously NEP expression in rat parietal cortex (Cx) and hippocampus (Hip) decreases with age and is also significantly reduced after prenatal hypoxia. Following the paradigms for enhancement of NEP expression and activity developed in cell culture, we analysed the efficacy of various compounds able to upregulate NEP using our model of prenatal hypoxia in rats. In addition to the previous data demonstrating that valproic acid can upregulate NEP expression both in neuroblastoma cells and in rat Cx and Hip we have further confirmed that caspase inhibitors can also restore NEP expression in rat Cx reduced after prenatal hypoxia. Here we also report that administration of a green tea catechin epigallocatechin-3-gallate (EGCG) to adult rats subjected to prenatal hypoxia increased NEP activity in blood plasma, Cx and Hip as well as improved memory performance in the 8-arm maze and novel object recognition tests. Moreover, EGCG administration led to an increased number of dendritic spines in the hippocampal CA1 area which correlated with memory enhancement. The data obtained allowed us to conclude that the decrease in the activity of the amyloid-degrading enzyme NEP, as well as a reduction in the number of labile interneuronal contacts in the hippocampus, contribute to early cognitive deficits caused by prenatal hypoxia and that there are therapeutic avenues to restore these deficits via NEP activation which could also be used for designing preventive strategies in AD.


Assuntos
Catequina/análogos & derivados , Hipóxia/tratamento farmacológico , Neprilisina/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Animais , Catequina/uso terapêutico , Linhagem Celular Tumoral , Córtex Cerebral/metabolismo , Cognição/efeitos dos fármacos , Dendritos/metabolismo , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Neprilisina/genética , Gravidez , Ratos Wistar , Regulação para Cima
4.
Dev Cell ; 48(6): 864-872.e7, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30827898

RESUMO

Dynamic coupling of microtubule ends to kinetochores, built on the centromeres of chromosomes, directs chromosome segregation during cell division. Here, we report that the evolutionarily ancient kinetochore-microtubule coupling machine, the KMN (Knl1/Mis12/Ndc80-complex) network, plays a critical role in neuronal morphogenesis. We show that the KMN network concentrates in microtubule-rich dendrites of developing sensory neurons that collectively extend in a multicellular morphogenetic event that occurs during C. elegans embryogenesis. Post-mitotic degradation of KMN components in sensory neurons disrupts dendritic extension, leading to patterning and functional defects in the sensory nervous system. Structure-guided mutations revealed that the molecular interface that couples kinetochores to spindle microtubules also functions in neuronal development. These results identify a cell-division-independent function for the chromosome-segregation machinery and define a microtubule-coupling-dependent event in sensory nervous system morphogenesis.


Assuntos
Cinetocoros/metabolismo , Microtúbulos/metabolismo , Morfogênese , Sistema Nervoso/embriologia , Sistema Nervoso/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Caenorhabditis elegans/embriologia , Proteínas de Caenorhabditis elegans/metabolismo , Dendritos/metabolismo , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Mitose
5.
Nat Neurosci ; 22(4): 556-564, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30911184

RESUMO

Heterozygous loss-of-function mutations in SHANK2 are associated with autism spectrum disorder (ASD). We generated cortical neurons from induced pluripotent stem cells derived from neurotypic and ASD-affected donors. We developed sparse coculture for connectivity assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed increases in dendrite length, dendrite complexity, synapse number, and frequency of spontaneous excitatory postsynaptic currents. These findings were phenocopied in gene-edited homozygous SHANK2 knockout cells and rescued by gene correction of an ASD SHANK2 mutation. Dendrite length increases were exacerbated by IGF1, TG003, or BDNF, and suppressed by DHPG treatment. The transcriptome in isogenic SHANK2 neurons was perturbed in synapse, plasticity, and neuronal morphogenesis gene sets and ASD gene modules, and activity-dependent dendrite extension was impaired. Our findings provide evidence for hyperconnectivity and altered transcriptome in SHANK2 neurons derived from ASD subjects.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Dendritos/patologia , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Transtorno do Espectro Autista/metabolismo , Técnicas de Cocultura , Dendritos/metabolismo , Potenciais Pós-Sinápticos Excitadores , Técnicas de Inativação de Genes , Haploinsuficiência , Humanos , Células-Tronco Pluripotentes Induzidas , Masculino , Plasticidade Neuronal , Neurônios/metabolismo , Transcriptoma
6.
Mol Brain ; 12(1): 19, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866998

RESUMO

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS [MIM 270550]) is an early-onset neurodegenerative disorder caused by mutations in the SACS gene. Over 200 SACS mutations have been identified. Most mutations lead to a complete loss of a sacsin, a large 520 kD protein, although some missense mutations are associated with low levels of sacsin expression. We previously showed that Sacs knock-out mice demonstrate early-onset ataxic phenotype with neurofilament bundling in many neuronal populations. To determine if the preservation of some mutated sacsin protein resulted in the same cellular and behavioral alterations, we generated mice expressing an R272C missense mutation, a homozygote mutation found in some affected patients. Though SacsR272C mice express 21% of wild type brain sacsin and sacsin is found in many neurons, they display similar abnormalities to Sacs knock-out mice, including the development of an ataxic phenotype, reduced Purkinje cell firing rates, and somatodendritic neurofilament bundles in Purkinje cells and other neurons. Together our results support that Sacs missense mutation largely lead to loss of sacsin function.


Assuntos
Ataxia/genética , Ataxia/fisiopatologia , Proteínas de Choque Térmico/genética , Mutação de Sentido Incorreto/genética , Potenciais de Ação , Animais , Sequência de Bases , Encéfalo/metabolismo , Encéfalo/patologia , Dendritos/metabolismo , Marcação de Genes , Proteínas de Choque Térmico/metabolismo , Homozigoto , Humanos , Filamentos Intermediários/metabolismo , Camundongos Endogâmicos C57BL , Atividade Motora , Debilidade Muscular/patologia , Fenótipo , Células de Purkinje/metabolismo , Células de Purkinje/patologia
7.
Nat Commun ; 10(1): 1331, 2019 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-30902970

RESUMO

GABAB receptors (GBRs) are key regulators of synaptic release but little is known about trafficking mechanisms that control their presynaptic abundance. We now show that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs. Of the three interacting proteins, selectively the genetic loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression. Proteomic and functional analyses revealed that APP associates with JIP and calsyntenin proteins that link the APP/GBR complex in cargo vesicles to the axonal trafficking motor. Complex formation with GBRs stabilizes APP at the cell surface and reduces proteolysis of APP to Aß, a component of senile plaques in Alzheimer's disease patients. Thus, APP/GBR complex formation links presynaptic GBR trafficking to Aß formation. Our findings support that dysfunctional axonal trafficking and reduced GBR expression in Alzheimer's disease increases Aß formation.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Transporte Axonal , Receptores de GABA-B/metabolismo , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Animais , Axônios/metabolismo , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Membrana Celular/metabolismo , Dendritos/metabolismo , Epitopos/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Cinesina/metabolismo , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteômica , Transdução de Sinais , Sinapses/metabolismo
8.
Neurochem Res ; 44(5): 1243-1251, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30875016

RESUMO

A majority of excitatory synapses in the brain are localized on the dendritic spines. Alterations of spine density and morphology are associated with many neurological diseases. Understanding the molecular mechanisms underlying spine formation is important for understanding these diseases. Kalirin7 (Kal-7) is localized to the postsynaptic side of excitatory synapses in the neurons. Overexpression of Kal-7 causes an increase in spine density whereas knockdown expression of endogenous Kal-7 results in a decrease in spine density in primary cultured cortical neurons. However, the mechanisms underlying Kal-7-mediated spine formation are not entirely clear. Cyclin-dependent kinase 5 (Cdk5) plays a vital role in the formation of spines and synaptic plasticity. Kal-7 is phosphorylated by CDK5 at Thr1590, the unique Cdk5 phosphorylation site in the Kal-7 protein. This study was to explore the role of CDK5-mediated phosphorylation of Kal-7 in spine formation and the underlying mechanisms. Our results showed expression of Kal-7T/D (mimicked phosphorylation), Kal-7T/A mutants (blocked phosphorylation) or wild-type (Wt) Kal-7 caused in a similar increase in spine density, while spine size of Wt Kal-7-expressing cortical neurons was bigger than that in Kal-7 T\A-expressing neurons, but smaller than that in Kal-7T/D-expressing neurons. The fluorescence intensity of NMDA receptor subunit NR2B (GluN2B) staining was stronger along the MAP2 positive dendrites of Kal-7T/D-expressing neurons than that in Kal-7T/A- or Wt Kal-7-expressing neurons. The fluorescence intensity of AMPA receptor subunit GluR1 (GluA1) staining showed the same trend as GluN2B staining. These findings suggest that Cdk5 affects the function of Kal-7 on spine morphology and function via GluN2B and GluA1 receptors during dendritic spine formation.


Assuntos
Quinase 5 Dependente de Ciclina/metabolismo , Dendritos/metabolismo , Espinhas Dendríticas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Animais , Hipocampo/metabolismo , Neurogênese/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Sinapses/metabolismo
9.
Nat Neurosci ; 22(3): 386-400, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30742117

RESUMO

Fragile X syndrome results from a loss of the RNA-binding protein fragile X mental retardation protein (FMRP). How FMRP regulates neuronal development and function remains unclear. Here we show that FMRP-deficient immature neurons exhibit impaired dendritic maturation, altered expression of mitochondrial genes, fragmented mitochondria, impaired mitochondrial function, and increased oxidative stress. Enhancing mitochondrial fusion partially rescued dendritic abnormalities in FMRP-deficient immature neurons. We show that FMRP deficiency leads to reduced Htt mRNA and protein levels and that HTT mediates FMRP regulation of mitochondrial fusion and dendritic maturation. Mice with hippocampal Htt knockdown and Fmr1-knockout mice showed similar behavioral deficits that could be rescued by treatment with a mitochondrial fusion compound. Our data unveil mitochondrial dysfunction as a contributor to the impaired dendritic maturation of FMRP-deficient neurons and suggest a role for interactions between FMRP and HTT in the pathogenesis of fragile X syndrome.


Assuntos
Dendritos/metabolismo , Giro Denteado/metabolismo , Proteína do X Frágil de Retardo Mental/metabolismo , Proteína Huntingtina/metabolismo , Dinâmica Mitocondrial , Animais , Giro Denteado/crescimento & desenvolvimento , Feminino , Proteína do X Frágil de Retardo Mental/genética , Técnicas de Silenciamento de Genes , Genes Mitocondriais , Proteína Huntingtina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo
10.
Nature ; 567(7746): 100-104, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30787434

RESUMO

Sensory experience in early postnatal life, during so-called critical periods, restructures neural circuitry to enhance information processing1. Why the cortex is susceptible to sensory instruction in early life and why this susceptibility wanes with age are unclear. Here we define a developmentally restricted engagement of inhibitory circuitry that shapes localized dendritic activity and is needed for vision to drive the emergence of binocular visual responses in the mouse primary visual cortex. We find that at the peak of the critical period for binocular plasticity, acetylcholine released from the basal forebrain during periods of heightened arousal directly excites somatostatin (SST)-expressing interneurons. Their inhibition of pyramidal cell dendrites and of fast-spiking, parvalbumin-expressing interneurons enhances branch-specific dendritic responses and somatic spike rates within pyramidal cells. By adulthood, this cholinergic sensitivity is lost, and compartmentalized dendritic responses are absent but can be re-instated by optogenetic activation of SST cells. Conversely, suppressing SST cell activity during the critical period prevents the normal development of binocular receptive fields by impairing the maturation of ipsilateral eye inputs. This transient cholinergic modulation of SST cells, therefore, seems to orchestrate two features of neural plasticity-somatic disinhibition and compartmentalized dendritic spiking. Loss of this modulation may contribute to critical period closure.


Assuntos
Potenciais de Ação , Período Crítico (Psicologia) , Dendritos/metabolismo , Córtex Visual/citologia , Córtex Visual/fisiologia , Acetilcolina/metabolismo , Animais , Sinalização do Cálcio , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Inibição Neural , Vias Neurais , Plasticidade Neuronal/fisiologia , Fenômenos Fisiológicos Oculares , Optogenética , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Somatostatina/metabolismo , Visão Binocular/fisiologia
11.
J Physiol Sci ; 69(3): 453-463, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30758780

RESUMO

The neuronal K+-Cl- cotransporter KCC2 maintains a low intracellular Cl- concentration and facilitates hyperpolarizing GABAA receptor responses. KCC2 also plays a separate role in stabilizing and enhancing dendritic spines in the developing nervous system. Using a conditional transgenic mouse strategy, we examined whether overexpression of KCC2 enhances dendritic spines in the adult nervous system and characterized the effects on spine dynamics in the motor cortex in vivo during rotarod training. Mice overexpressing KCC2 showed significantly increased spine density in the apical dendrites of layer V pyramidal neurons, measured in vivo using two-photon imaging. During modest accelerated rotarod training, mice overexpressing KCC2 displayed enhanced spine formation rates, greater balancing skill at higher rotarod speeds and a faster rate of learning in this ability. Our results demonstrate that KCC2 enhances spine density and dynamics in the adult nervous system and suggest that KCC2 may play a role in experience-dependent synaptic plasticity.


Assuntos
Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/fisiologia , Aprendizagem/fisiologia , Córtex Motor/metabolismo , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Simportadores/metabolismo , Animais , Dendritos/metabolismo , Dendritos/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Sinapses/metabolismo , Sinapses/fisiologia
12.
Proc Natl Acad Sci U S A ; 116(11): 5126-5134, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30804200

RESUMO

Sensory neurons perceive environmental cues and are important of organismal survival. Peripheral sensory neurons interact intimately with glial cells. While the function of axonal ensheathment by glia is well studied, less is known about the functional significance of glial interaction with the somatodendritic compartment of neurons. Herein, we show that three distinct glia cell types differentially wrap around the axonal and somatodendritic surface of the polymodal dendritic arborization (da) neuron of the Drosophila peripheral nervous system for detection of thermal, mechanical, and light stimuli. We find that glial cell-specific loss of the chromatin modifier gene dATRX in the subperineurial glial layer leads to selective elimination of somatodendritic glial ensheathment, thus allowing us to investigate the function of such ensheathment. We find that somatodendritic glial ensheathment regulates the morphology of the dendritic arbor, as well as the activity of the sensory neuron, in response to sensory stimuli. Additionally, glial ensheathment of the neuronal soma influences dendritic regeneration after injury.


Assuntos
Dendritos/metabolismo , Drosophila melanogaster/metabolismo , Neuroglia/metabolismo , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Animais , Axônios/metabolismo , Axônios/efeitos da radiação , Caspases/metabolismo , DNA Helicases/metabolismo , Dendritos/efeitos da radiação , Proteínas de Drosophila/metabolismo , Ativação Enzimática/efeitos da radiação , Luz , Neuroglia/efeitos da radiação , Células Receptoras Sensoriais/efeitos da radiação
13.
Nat Commun ; 10(1): 568, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718476

RESUMO

Endoplasmic reticulum (ER) is characterized by interconnected tubules and sheets. Neuronal ER adopts specific morphology in axons, dendrites and soma. Here we study mechanisms underlying ER morphogenesis in a C. elegans sensory neuron PVD. In PVD soma and dendrite branch points, ER tubules connect to form networks. ER tubules fill primary dendrites but only extend to some but not all dendritic branches. We find that the Atlastin-1 ortholog, atln-1 is required for neuronal ER morphology. In atln-1 mutants with impaired GTPase activity, ER networks in soma and dendrite branch points are reduced and replaced by tubules, and ER tubules retracted from high-order dendritic branches, causing destabilized microtubule in these branches. The abnormal ER morphology likely causes defects in mitochondria fission at dendritic branch points. Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP) patients show similar ER phenotypes, suggesting that neuronal ER impairment contributes to HSP disease pathogenesis.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Dendritos/metabolismo , Retículo Endoplasmático/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Dendritos/genética , Retículo Endoplasmático/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microtúbulos/metabolismo , Paraplegia Espástica Hereditária/genética , Paraplegia Espástica Hereditária/metabolismo
14.
Mol Cell Neurosci ; 95: 79-85, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30763690

RESUMO

Trisomy 21, also known as Down syndrome (DS), is the most frequent genetic cause of intellectual impairment. In mouse models of DS, deficits in hippocampal synaptic plasticity have been observed, in conjunction with alterations to local dendritic translation that are likely to influence plasticity, learning and memory. Here we show that expression of a local translational regulator, the Cytoplasmic Polyadenylation Element Binding Protein 1 (CPEB1), is enhanced in hippocampal neurons from the Ts1Cje DS mouse model. Interestingly, this protein, which is also involved in dendritic mRNA transport, is overexpressed in dendrites of neurons derived from DS human induced pluripotent stem cells (hIPSCs). Moreover, there is an increase in the mRNA levels of α-Calmodulin Kinase II (α-CaMKII) and Microtubule-associated protein 1B (MAP1B), two dendritic mRNAs, in Ts1Cje synaptoneurosomes. Taking into account the fundamental role of CPEB1 protein and its target mRNAs in synaptic plasticity, these data could be relevant to the intellectual impairment in the context of DS.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Síndrome de Down/metabolismo , Hipocampo/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Dendritos/metabolismo , Síndrome de Down/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/citologia
15.
Nat Commun ; 10(1): 813, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30778062

RESUMO

Neurons are highly polarized cells with distinct protein compositions in axonal and dendritic compartments. Cellular mechanisms controlling polarized protein sorting have been described for mature nervous system but little is known about the segregation in newly differentiated neurons. In a forward genetic screen for regulators of Drosophila brain circuit development, we identified mutations in SPT, an evolutionary conserved enzyme in sphingolipid biosynthesis. Here we show that reduced levels of sphingolipids in SPT mutants cause axonal morphology defects similar to loss of cell recognition molecule Dscam. Loss- and gain-of-function studies show that neuronal sphingolipids are critical to prevent aggregation of axonal and dendritic Dscam isoforms, thereby ensuring precise Dscam localization to support axon branch segregation. Furthermore, SPT mutations causing neurodegenerative HSAN-I disorder in humans also result in formation of stable Dscam aggregates and axonal branch phenotypes in Drosophila neurons, indicating a causal link between developmental protein sorting defects and neuronal dysfunction.


Assuntos
Axônios/fisiologia , Moléculas de Adesão Celular/metabolismo , Proteínas de Drosophila/metabolismo , Esfingolipídeos/metabolismo , Animais , Animais Geneticamente Modificados , Moléculas de Adesão Celular/genética , Dendritos/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Masculino , Corpos Pedunculados/citologia , Corpos Pedunculados/metabolismo , Mutação , Domínios Proteicos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico , Serina C-Palmitoiltransferase/genética , Serina C-Palmitoiltransferase/metabolismo
16.
Transl Res ; 207: 1-18, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30731068

RESUMO

Acamprosate, also known as N-acetyl homotaurine, is an N-methyl-d-aspartate receptor antagonist that is used for treating alcohol dependence. Although the exact mechanism of acamprosate has not been clearly established, it appears to work by promoting a balance between the excitatory and inhibitory neurotransmitters, glutamate, and gamma-aminobutyric acid, respectively. Several studies have demonstrated that acamprosate provides neuroprotection against ischemia-induced brain injury. However, no studies have been performed evaluating the effect of acamprosate on traumatic brain injury (TBI). In the present study, we sought to evaluate the therapeutic potential of acamprosate to protect against neuronal death following TBI. Rats were given oral acamprosate (200 mg/kg/d for 2weeks) and then subjected to a controlled cortical impact injury localized over the parietal cortex. Histologic analysis was performed at 3hours, 24hours, and 7days after TBI. We found that acamprosate treatment reduced the concentration of vesicular glutamate and zinc in the hippocampus. Consequently, this reduced vesicular glutamate and zinc level resulted in a reduction of reactive oxygen species production after TBI. When evaluated 24hours after TBI, acamprosate administration reduced the number of degenerating neurons, zinc accumulation, blood-brain barrier disruption, neutrophil infiltration, and dendritic loss. Acamprosate also reduced glial activation and neuronal loss at 7days after TBI. In addition, acamprosate rescued TBI-induced neurologic and cognitive dysfunction. The present study demonstrates that acamprosate attenuates TBI-induced brain damage by depletion of vesicular glutamate and zinc levels. Therefore, this study suggests that acamprosate may have high therapeutic potential for prevention of TBI-induced neuronal death.


Assuntos
Acamprosato/uso terapêutico , Alcoolismo/tratamento farmacológico , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/prevenção & controle , Vesículas Citoplasmáticas/metabolismo , Neurônios/patologia , Zinco/metabolismo , Acamprosato/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Lesões Encefálicas Traumáticas/fisiopatologia , Morte Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Vesículas Citoplasmáticas/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Dendritos/patologia , Hipocampo/metabolismo , Masculino , Modelos Biológicos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Infiltração de Neutrófilos/efeitos dos fármacos , Ratos Sprague-Dawley , Superóxidos/metabolismo
17.
Int J Mol Sci ; 20(4)2019 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-30781689

RESUMO

Aging is characterized by increased inflammation and deterioration of the cellular stress responses such as the oxidant/antioxidant equilibrium, DNA damage repair fidelity, and telomeric attrition. All these factors contribute to the increased radiation sensitivity in the elderly as shown by epidemiological studies of the Japanese atomic bomb survivors. There is a global increase in the aging population, who may be at increased risk of exposure to ionizing radiation (IR) as part of cancer therapy or accidental exposure. Therefore, it is critical to delineate the factors that exacerbate age-related radiation sensitivity and neurocognitive decline. The transcription factor CCAAT enhancer binding protein delta (C/EBPδ) is implicated with regulatory roles in neuroinflammation, learning, and memory, however its role in IR-induced neurocognitive decline and aging is not known. The purpose of this study was to delineate the role of C/EBPδ in IR-induced neurocognitive decline in aged mice. We report that aged Cebpd-/- mice exposed to acute IR exposure display impairment in short-term memory and spatial memory that correlated with significant alterations in the morphology of neurons in the dentate gyrus (DG) and CA1 apical and basal regions. There were no significant changes in the expression of inflammatory markers. However, the expression of superoxide dismutase 2 (SOD2) and catalase (CAT) were altered post-IR in the hippocampus of aged Cebpd-/- mice. These results suggest that Cebpd may protect from IR-induced neurocognitive dysfunction by suppressing oxidative stress in aged mice.


Assuntos
Proteína delta de Ligação ao Facilitador CCAAT/deficiência , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Radiação Ionizante , Envelhecimento , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Dendritos/metabolismo , Giro Denteado/patologia , Mediadores da Inflamação/metabolismo , Aprendizagem em Labirinto , Memória de Curto Prazo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Memória Espacial , Extratos de Tecidos
18.
Development ; 146(2)2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30642835

RESUMO

In the Drosophila visual system, T4/T5 neurons represent the first stage of computation of the direction of visual motion. T4 and T5 neurons exist in four subtypes, each responding to motion in one of the four cardinal directions and projecting axons into one of the four lobula plate layers. However, all T4/T5 neurons share properties essential for sensing motion. How T4/T5 neurons acquire their properties during development is poorly understood. We reveal that the transcription factors SoxN and Sox102F control the acquisition of properties common to all T4/T5 neuron subtypes, i.e. the layer specificity of dendrites and axons. Accordingly, adult flies are motion blind after disruption of SoxN or Sox102F in maturing T4/T5 neurons. We further find that the transcription factors Ato and Dac are redundantly required in T4/T5 neuron progenitors for SoxN and Sox102F expression in T4/T5 neurons, linking the transcriptional programmes specifying progenitor identity to those regulating the acquisition of morphological properties in neurons. Our work will help to link structure, function and development in a neuronal type performing a computation that is conserved across vertebrate and invertebrate visual systems.


Assuntos
Movimento Celular , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Neurônios/citologia , Neurônios/metabolismo , Transcrição Genética , Animais , Axônios/metabolismo , Movimento Celular/genética , Dendritos/metabolismo , Proteínas de Drosophila/metabolismo , Inativação Gênica , Atividade Motora , Neurópilo/metabolismo , Lobo Óptico de Animais não Mamíferos/embriologia , Lobo Óptico de Animais não Mamíferos/metabolismo , Ativação Transcricional/genética
19.
Dev Cell ; 48(2): 229-244.e4, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30661986

RESUMO

The mechanisms that pattern and maintain dendritic arbors are key to understanding the principles that govern nervous system assembly. The activity of presynaptic axons has long been known to shape dendrites, but activity-independent functions of axons in this process have remained elusive. Here, we show that in Caenorhabditis elegans, the axons of the ALA neuron control guidance and extension of the 1° dendrites of PVD somatosensory neurons independently of ALA activity. PVD 1° dendrites mimic ALA axon guidance defects in loss-of-function mutants for the extracellular matrix molecule MIG-6/Papilin or the UNC-6/Netrin pathway, suggesting that axon-dendrite adhesion is important for dendrite formation. We found that the SAX-7/L1CAM cell adhesion molecule engages in distinct molecular mechanisms to mediate extensions of PVD 1° dendrites and maintain the ALA-PVD axon-dendritic fascicle, respectively. Thus, axons can serve as critical scaffolds to pattern and maintain dendrites through contact-dependent but activity-independent mechanisms.


Assuntos
Axônios/metabolismo , Moléculas de Adesão Celular/metabolismo , Dendritos/metabolismo , Plasticidade Neuronal/fisiologia , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo
20.
Neuron ; 101(2): 204-206, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30653934

RESUMO

Two papers in Cell uncover reciprocal crosstalk of local translation and mitochondria in neurons. Rangaraju et al. (2019) observe tethered compartments of stable mitochondria in dendrites that provide a local energy supply for mRNA translation at synapses. Cioni et al. (2019) report a novel association of axonal RNA granules with Rab7a-late endosomes that provides a platform for local translation supporting mitochondria.


Assuntos
Axônios/metabolismo , Dendritos/metabolismo , Mitocôndrias/fisiologia , Neurônios/citologia , Biossíntese de Proteínas/fisiologia , Animais , Transporte Axonal , Axônios/ultraestrutura , Plasticidade Celular , Dendritos/ultraestrutura , Neurônios/ultraestrutura , RNA Mensageiro/metabolismo
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