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1.
Neurourol Urodyn ; 38(5): 1250-1260, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30989724

RESUMO

AIMS: Central sensitization playsimportant roles in cyclophosphamide (CYP)-induced cystitis. In addition, as a visceral pain, CYP-induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin-1 (Nrg1)-ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP-induced cystitis is unclear. This study aimed to determine whether and how Nrg1-ErbB signaling modulates mechanical allodynia in a CYP-induced cystitis rat model. METHODS: Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1-ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von-Frey filaments using the up-down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1-ErbB signaling, Iba-1, p-p38, and IL-1ß in the L6-S1 spinal dorsal horn (SDH). RESULTS: We observed upregulation of Nrg1-ErbB signaling as well as overexpression of the microglia activation markers Iba-1 and p-p38 and the proinflammatory factor, interleukin-1ß (IL-1ß), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of IL-1ß. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. CONCLUSIONS: Nrg1-ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP-induced cystitis. Our study showed that modulation of Nrg1-ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.


Assuntos
Cistite/induzido quimicamente , Hiperalgesia/induzido quimicamente , Microglia , Neuregulina-1/fisiologia , Proteínas Oncogênicas v-erbB/fisiologia , Animais , Cistite/complicações , Cistite/tratamento farmacológico , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Injeções Espinhais , Ativação de Macrófagos , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
2.
Hepatology ; 70(6): 2193-2203, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31034656

RESUMO

Sarcopenia is a common complication of cirrhosis and is defined as a progressive and generalized loss of skeletal muscle mass, strength, and function. Sarcopenia is associated with poor prognosis and increased mortality. How sarcopenia and muscle wasting relate to such poor outcomes requires looking beyond the overt muscle loss and at this entity as a systemic disease that affects muscles of vital organs including cardiac and respiratory muscles. This review explores the pathophysiological pathways and mechanisms that culminate in poor outcomes associated with sarcopenia. This provides a launching pad to identify potential targets for therapeutic intervention and optimization to improve patient outcomes.


Assuntos
Cirrose Hepática/complicações , Músculo Esquelético/metabolismo , Sarcopenia/etiologia , Trifosfato de Adenosina/metabolismo , Humanos , Inflamação/complicações , Resistência à Insulina , Fibras Musculares Esqueléticas/metabolismo , Miócitos Cardíacos/fisiologia , Neuregulina-1/fisiologia , Sarcopenia/terapia
3.
FASEB J ; 33(7): 7833-7851, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30912977

RESUMO

C-type synaptic boutons (C-boutons) provide cholinergic afferent input to spinal cord motor neurons (MNs), which display an endoplasmic reticulum (ER)-related subsurface cistern (SSC) adjacent to their postsynaptic membrane. A constellation of postsynaptic proteins is clustered at C-boutons, including M2 muscarinic receptors, potassium channels, and σ-1 receptors. In addition, we previously found that neuregulin (NRG)1 is associated with C-boutons at postsynaptic SSCs, whereas its ErbB receptors are located in the presynaptic compartment. C-bouton-mediated regulation of MN excitability has been implicated in MN disease, but NRG1-mediated functions and the impact of various pathologic conditions on C-bouton integrity have not been studied in detail. Here, we investigated changes in C-boutons after electrical stimulation, pharmacological treatment, and peripheral nerve axotomy. SSC-linked NRG1 clusters were severely disrupted in acutely stressed MNs and after tunicamycin-induced ER stress. In axotomized MNs, C-bouton loss occurred in concomitance with microglial recruitment and was prevented by the ER stress inhibitor salubrinal. Activated microglia displayed a positive chemotaxis to C-boutons. Analysis of transgenic mice overexpressing NRG1 type I and type III isoforms in MNs indicated that NRG1 type III acts as an organizer of SSC-like structures, whereas NRG1 type I promotes synaptogenesis of presynaptic cholinergic terminals. Moreover, MN-derived NRG1 signals may regulate the activity of perineuronal microglial cells. Together, these data provide new insights into the molecular and cellular pathology of C-boutons in MN injury and suggest that distinct NRG1 isoform-mediated signaling functions regulate the complex matching between pre- and postsynaptic C-bouton elements.-Salvany, S., Casanovas, A., Tarabal, O., Piedrafita, L., Hernández, S., Santafé, M., Soto-Bernardini, M. C., Calderó, J., Schwab, M. H., Esquerda, J. E. Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair.


Assuntos
Células do Corno Anterior/fisiologia , Fibras Nervosas Amielínicas/fisiologia , Regeneração Nervosa/fisiologia , Neuregulina-1/fisiologia , Terminações Pré-Sinápticas/fisiologia , Nervo Isquiático/lesões , Animais , Axotomia , Fibras Colinérgicas/fisiologia , Cinamatos/farmacologia , Estimulação Elétrica , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Retículo Endoplasmático Liso/fisiologia , Retículo Endoplasmático Liso/ultraestrutura , Camundongos , Camundongos Transgênicos , Microglia/fisiologia , Compressão Nervosa , Neuregulina-1/genética , Terminações Pré-Sinápticas/efeitos dos fármacos , Isoformas de Proteínas/fisiologia , Nervo Isquiático/fisiologia , Transdução de Sinais/fisiologia , Frações Subcelulares/química , Tioureia/análogos & derivados , Tioureia/farmacologia , Tunicamicina/toxicidade , Vacúolos/metabolismo , Vacúolos/ultraestrutura
4.
Hum Mol Genet ; 28(8): 1260-1273, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30535360

RESUMO

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 (NRG1) type III regulate Schwann cell fate and myelination. Here we ask if modulating NRG1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we improved the myelination defects by early overexpression of NRG1 type III. Surprisingly, the improvement was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 and oligodendrocyte myelin glycoprotein. We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial NRG1 type III signaling has beneficial effects and improves myelination defects during development in a model of CHN.


Assuntos
Bainha de Mielina/metabolismo , Neuregulina-1/genética , Neuregulina-1/fisiologia , Potenciais de Ação , Animais , Axônios/metabolismo , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/fisiopatologia , Modelos Animais de Doenças , Técnicas de Introdução de Genes/métodos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Transgênicos , Proteínas Quinases Ativadas por Mitógeno/genética , Neuregulina-1/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Nervos Periféricos/metabolismo , Células de Schwann/metabolismo , Transdução de Sinais/fisiologia
5.
Proc Natl Acad Sci U S A ; 115(46): E10979-E10987, 2018 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30373842

RESUMO

Effector-triggered immunity (ETI) in plants involves a large family of nucleotide-binding leucine-rich repeat (NLR) immune receptors, including Toll/IL-1 receptor-NLRs (TNLs) and coiled-coil NLRs (CNLs). Although various NLR immune receptors are known, a mechanistic understanding of NLR function in ETI remains unclear. The TNL Recognition of XopQ 1 (Roq1) recognizes the effectors XopQ and HopQ1 from Xanthomonas and Pseudomonas, respectively, which activates resistance to Xanthomonas euvesicatoria and Xanthomonas gardneri in an Enhanced Disease Susceptibility 1 (EDS1)-dependent way in Nicotiana benthamiana In this study, we found that the N. benthamiana N requirement gene 1 (NRG1), a CNL protein required for the tobacco TNL protein N-mediated resistance to tobacco mosaic virus, is also essential for immune signaling [including hypersensitive response (HR)] triggered by the TNLs Roq1 and Recognition of Peronospora parasitica 1 (RPP1), but not by the CNLs Bs2 and Rps2, suggesting that NRG1 may be a conserved key component in TNL signaling pathways. Besides EDS1, Roq1 and NRG1 are necessary for resistance to Xanthomonas and Pseudomonas in N. benthamiana NRG1 functions downstream of Roq1 and EDS1 and physically associates with EDS1 in mediating XopQ-Roq1-triggered immunity. Moreover, RNA sequencing analysis showed that XopQ-triggered gene-expression profile changes in N. benthamiana were almost entirely mediated by Roq1 and EDS1 and were largely regulated by NRG1. Overall, our study demonstrates that NRG1 is a key component that acts downstream of EDS1 to mediate various TNL signaling pathways, including Roq1 and RPP1-mediated HR, resistance to Xanthomonas and Pseudomonas, and XopQ-regulated transcriptional changes in N. benthamiana.


Assuntos
Tabaco/genética , Tabaco/metabolismo , Subpopulações de Linfócitos B/metabolismo , Proteínas de Ligação a DNA , Proteínas NLR/metabolismo , Neuregulina-1/genética , Neuregulina-1/fisiologia , Doenças das Plantas , Imunidade Vegetal , Proteínas de Plantas/genética , Domínios Proteicos , Proteínas/genética , Pseudomonas , Transdução de Sinais , Transcriptoma , Xanthomonas
6.
Mol Biol Rep ; 45(6): 1611-1619, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30178217

RESUMO

Sepsis-induced skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass. Cytokine-induced apoptosis and impaired myogenesis play key roles in the development of this condition. However, the complete underlying mechanism remains largely unknown. Neuregulins are glial growth factors essential for myogenesis that regulate muscle metabolism. We investigated the role of neuregulin-1ß (NRG-1ß) in sepsis-induced apoptosis and myogenesis in skeletal muscle using a serum-based in vitro sepsis model. C2C12 myoblasts were differentiated by treatment with proliferative medium for 7 days. Then, cells were treated with 2% sham mouse serum, 1 nM NRG-1ß in 2% sham mouse serum, 2% septic mouse serum (SMS), or 1 nM NRG-1ß in 2% SMS. Exposure to SMS induced apoptosis, impaired myogenesis, and downregulated PPARγ. NRG-1ß co-incubation remedied all these effects and inhibited NF-κB transcriptional activity. A specific PPARγ antagonist (GW9662) was also administered as a 2-h pretreatment to block PPARγ-mediated signaling and appeared to attenuate the effects of NRG-1ß. Taken together, our results demonstrate that NRG-1ß functions via a PPARγ/NF-κB-dependent pathway to modulate myogenesis and protect against apoptosis in SMS-treated C2C12 myotubes.


Assuntos
Desenvolvimento Muscular/efeitos dos fármacos , Neuregulina-1/fisiologia , Animais , Apoptose/efeitos dos fármacos , Atrofia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo , Feminino , Regulação da Expressão Gênica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/fisiologia , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético , Mioblastos/metabolismo , NF-kappa B/metabolismo , Neuregulina-1/genética , PPAR gama/metabolismo , Sepse/metabolismo , Transdução de Sinais/efeitos dos fármacos
7.
Cell Signal ; 52: 23-34, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30165102

RESUMO

The interplay of ErbB receptor homo- and heterodimers plays a crucial role in the pathology of breast cancer since activated signal transduction cascades coordinate proliferation, survival and migration of cells. EGF and ß-Heregulin are well characterised ligands known to induce ErbB homo- and heterodimerisation, which have been associated with disease progression. In the present study, we investigated the impact of both factors on the migration of MDA-NEO and MDA-HER2 human breast cancer cells. MDA-NEO cells are positive for EGFR and HER3, while MDA-HER2 cells express EGFR, HER2 and HER3. Cell migration analysis revealed that ß-Heregulin potently impaired EGF induced migration in both cell lines. Western blot studies showed that both ErbB receptor and PLC-γ1 tyrosine phosphorylation levels were diminished in EGF and ß-Heregulin co-treated MDA-NEO and MDA-HER2 cells, which was further correlated to a significantly impaired calcium influx. Our data indicate that EGF and HRG may interfere with each other for receptor binding and dimerisation, which ultimately has an impact on signalling outcome.


Assuntos
Neoplasias da Mama/patologia , Fator de Crescimento Epidérmico/fisiologia , Receptores ErbB/metabolismo , Neuregulina-1/fisiologia , Fosfolipase C gama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Ensaios de Migração Celular , Movimento Celular , Feminino , Humanos , Invasividade Neoplásica , Fosforilação , Multimerização Proteica , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Transdução de Sinais
8.
Sci Rep ; 8(1): 9855, 2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29959353

RESUMO

Deficits in neurite outgrowth and synaptogenesis have been recognized as an underlying developmental aetiology of psychosis. Electrical stimulation promotes neuronal induction including neurite outgrowth and branching. However, the effect of electrical stimulation using 3D electrodes on neurite outgrowth and synaptogenesis has not been explored. This study examined the effect of 3D electrical stimulation on 3D primary cortical neuronal cultures. 3D electrical stimulation improved neurite outgrowth in 3D neuronal cultures from both wild-type and NRG1-knockout (NRG1-KO) mice. The expression of synaptophysin and PSD95 were elevated under 3D electrical stimulation. Interestingly, 3D electrical stimulation also improved neural cell aggregation as well as the expression of PSA-NCAM. Our findings suggest that the 3D electrical stimulation system can rescue neurite outgrowth deficits in a 3D culturing environment, one that more closely resembles the in vivo biological system compared to more traditionally used 2D cell culture, including the observation of cell aggregates as well as the upregulated PSA-NCAM protein and transcript expression. This study provides a new concept for a possible diagnostic platform for neurite deficits in neurodevelopmental diseases, as well as a viable platform to test treatment options (such as drug delivery) in combination with electrical stimulation.


Assuntos
Córtex Cerebral/citologia , Estimulação Elétrica , Neurogênese/fisiologia , Crescimento Neuronal/fisiologia , Neurônios/citologia , Polímeros/administração & dosagem , Sinapses/fisiologia , Animais , Técnicas de Cultura de Células , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuregulina-1/fisiologia , Neurogênese/efeitos dos fármacos , Crescimento Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Polímeros/química , Regeneração , Sinapses/efeitos dos fármacos
9.
Magn Reson Imaging ; 53: 63-70, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30021123

RESUMO

Stroke is a devastating neurovascular disorder that results in damage to neurons and white matter tracts. It has been previously demonstrated that neuregulin-1 (NRG-1) protects neurons from ischemic injury following stroke. Here, diffusion tensor imaging (DTI) was utilized to characterize the effects of NRG-1 treatment on cererbral infarction and integrity of white matter after ischemic insult using a permanent middle celebral artery occlusion (pMCAo) rat model. In the present study, sixteen Sprague-Dawley rats underwent pMCAo surgery and received either a single intra-arterial bolus (20 µg/kg) dose of NRG-1 or saline immediately prior to pMCAo. MRI including T2-weighted imaging and DTI was performed in the first 3 h post stroke, and repeated 48 h later. It is found that the stroke infarction was significantly reduced in the NRG-1 treated group. Also, NRG-1 prevented the reduction of fractional anisotropy (FA) in white matter tracts of fornix and corpus callosum (CC), indicating its protection of CC and fornix white matter bundles from ischemia insult. As a conclusion, the present DTI results demonstrate that NRG-1 has significantly neuroprotective effects in both cerebral cortex and white matter including corpus callosum and fornix during acute stroke. In particular, NRG-1 is more effective on stroke lesion with mild ischemia. As CC and fornix white matter bundles play critical roles in transcallosal connectivity and hippocampal projections respectively in the central nervous system, the findings could provide complementary information for better understanding the biological mechanism of NRG-1's neuroprotection in ischemic tissues and neurobehavioral effects.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Imagem de Tensor de Difusão , Neuregulina-1/fisiologia , Neuroproteção , Animais , Anisotropia , Córtex Cerebral/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Fórnice/diagnóstico por imagem , Isquemia , Imagem por Ressonância Magnética , Masculino , Neurônios/metabolismo , Fármacos Neuroprotetores , Ratos , Ratos Sprague-Dawley , Acidente Vascular Cerebral , Substância Branca
10.
J Pharmacol Sci ; 137(2): 146-153, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29914798

RESUMO

The amyloid precursor protein (APP) is a key molecule in Alzheimer's disease. The prevailing view is that APP is initially transported to the plasma membrane as a full-length protein. Its localization at the cell surface can trigger downstream signaling and APP cleavage. Our previous work has shown that Neuregulin 1 (NRG1) has neuroprotective effects in an Alzheimer's disease model. In the present study, we examine whether NRG1 signaling is involved in APP expression and non-amyloidogenic processing in neuronal cells. Here we show that NRG1 increased the cell surface expression of APP without changing the total amount of APP mRNA or protein expression in SH-SY5Y cells and in rat primary cortical neurons. In addition, NRG1 significantly increased the levels of the secreted form of APP, sAPPα, in the conditioned media but did not change the expression of ADAM10 on the cell surface or in the cell lysates. Furthermore, we found that the protein level of NRG1 was reduced in the hippocampus of Alzheimer's disease (AD) patients. Our results demonstrate that NRG1 increased APP expression on the cell surface and sAPPα secretion into the media of neuronal cell cultures. Taken together, these results suggest a role for NRG1 in non-amyloidogenic processing.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Neuregulina-1/fisiologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Proteína ADAM10/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Membrana Celular/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Expressão Gênica/genética , Proteínas de Membrana/metabolismo , Neuregulina-1/metabolismo , Fragmentos de Peptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/metabolismo
11.
Pharmacol Biochem Behav ; 170: 64-70, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29750976

RESUMO

Mice with a mutation in the transmembrane domain of the schizophrenia risk gene, neuregulin 1 (Nrg1 TM HET), are more susceptible to the neuro-behavioural effects of Δ9-tetrahydrocannabinol (D9-THC), the principal psychoactive component in cannabis. However, NRG1 is transcriptionally complex with over 30 different isoforms, most of which carry a transmembrane domain, raising the question which NRG1 isoform(s) may contribute to this phenotype. Type III NRG1/Nrg1 is the most brain abundant isoform and brain studies have identified increased levels of type III NRG1 mRNA in humans carrying a NRG1 risk haplotype for schizophrenia. To investigate whether mice heterozygous for type III Nrg1 (i.e. knockout: type III Nrg1+/-) are more susceptible to the behavioural effects of acute doses of D9-THC, we injected male mice with either vehicle or D9-THC (3 or 10 mg/kg) before testing them for locomotion, anxiety, social interaction, and sensorimotor gating. Acute D9-THC led to reduced locomotion and reduced social interaction, but increased anxiety in mice. Furthermore, type III Nrg1 males displayed a robust deficit in sensorimotor gating and demonstrated reduced following during social interaction across drug conditions. However, they did not show a change in behavioural susceptibility to acute D9-THC compared to controls. These results reinforce the validity of type III Nrg1+/- mice for schizophrenia research and suggest that loss of function of type III Nrg1 may not be responsible for the exaggerated response to acute D9-THC observed in heterozygous Nrg1 TM mice. This highlights the importance of careful consideration of Nrg1 isoform type differences.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dronabinol/toxicidade , Neuregulina-1/fisiologia , Animais , Comportamento Exploratório/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Comportamento Social
12.
Dev Dyn ; 247(7): 888-902, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29516589

RESUMO

BACKGROUND: Trunk neural crest cells migrate rapidly along characteristic pathways within the developing vertebrate embryo. Proper trunk neural crest cell migration is necessary for the morphogenesis of much of the peripheral nervous system, melanocytes, and the adrenal medulla. Numerous molecules help guide trunk neural crest cell migration throughout the early embryo. RESULTS: The trophic factor NRG1 is a chemoattractant through in vitro chemotaxis assays and in vivo silencing via a DN-erbB receptor. Interestingly, we also observed changes in migratory responses consistent with a chemokinetic effect of NRG1 in trunk neural crest velocity. CONCLUSIONS: NRG1 is a trunk neural crest cell chemoattractant and chemokinetic molecule. Developmental Dynamics 247:888-902, 2018.. © 2018 Wiley Periodicals, Inc.


Assuntos
Fatores Quimiotáticos/fisiologia , Crista Neural/citologia , Neuregulina-1/fisiologia , Animais , Movimento Celular , Quimiocinas/fisiologia , Quimiotaxia , Embrião de Galinha , Morfogênese
13.
Pharmacol Res ; 130: 12-24, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29427771

RESUMO

The neurotrophic factors neuregulins (NRGs) and their receptors, ErbB tyrosine kinases, regulate neurotransmission, synaptic plasticity and cognitive functions and their alterations have been associated to different neuropsychiatric disorders. Group 1 metabotropic glutamate receptors (mGluRI)-dependent mechanisms are also altered in animal models of neuropsychiatric diseases, especially mGluRI-induced glutamatergic long-term depression (mGluRI-LTD), a form of synaptic plasticity critically involved in learning and memory. Despite this evidence, a potential link between NRGs/ErbB signalling and mGluRI-LTD has never been considered. Here, we aimed to test the hypothesis that NRGs/ErbB signalling regulates mGluRI functions in the hippocampus, thus controlling CA1 pyramidal neurons excitability and synaptic plasticity as well as mGluRI-dependent behaviors. We investigated the functional interaction between NRG1/ErbB signalling and mGluRI in hippocampal CA1 pyramidal neurons, by analyzing the effect of a pharmacological modulation of NRG1/ErbB signalling on the excitation of pyramidal neurons and on the LTD at CA3-CA1 synapses induced by an mGluRI agonist. Furthermore, we verified the involvement of ErbB signalling in mGluRI-dependent learning processes, by evaluating the consequence of an intrahippocampal in vivo injection of a pan-ErbB inhibitor in the object recognition test in mice, a learning task dependent on hippocampal mGluRI. We found that NRG1 potentiates mGluRI-dependent functions on pyramidal neurons excitability and synaptic plasticity at CA3-CA1 synapses. Further, endogenous ErbB signalling per se regulates, through mGluRI, neuronal excitability and LTD in CA1 pyramidal neurons, since ErbB inhibition reduces mGluRI-induced neuronal excitation and mGluRI-LTD. In vivo intrahippocampal injection of the ErbB inhibitor, PD158780, impairs mGluRI-LTD at CA3-CA1 synapses and affects the exploratory behavior in the object recognition test. Thus, our results identify a key role for NRG1/ErbB signalling in the regulation of hippocampal mGluRI-dependent synaptic and cognitive functions, whose alteration might contribute to the pathogenesis of different brain diseases.


Assuntos
Receptores ErbB/fisiologia , Hipocampo/fisiologia , Neuregulina-1/fisiologia , Células Piramidais/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Animais , Depressão Sináptica de Longo Prazo , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Reconhecimento Psicológico
14.
Am J Med Genet B Neuropsychiatr Genet ; 177(2): 257-266, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28556469

RESUMO

Neuregulins, a four-member family of epidermal growth factor-like signaling molecules, have been studied for over two decades. They were first implicated in schizophrenia in 2002 with the detection of linkage and association at the NRG1 locus followed after a few years by NRG3. However, the associations with disease have not been very consistently observed. In contrast, association of NGR3 variants with disease presentation, specifically the presence of delusions, has been more consistent. This appears to be mediated by quantitative changes in the alternative splicing of the gene, which has also been consistently observed. Additional diseases and phenotypes, psychiatric or not, have also been connected with NRG3. These results demonstrate two important aspects of behavioral genetics research. The first is that if we only consider simple risk and fail to examine the details of each patient's individual phenotype, we will miss important insights on the disease biology. This is an important aspect of the goals of precision medicine. The second is that the functional consequences of variants are often more complex than simple alterations in levels of transcription of a particular gene, including, among others, regulation of alternative splicing. To accurately model and understand the biological consequences of phenotype-associated genetic variants, we need to study the biological consequences of each specific variant. Simply studying the consequences of a null allele of the orthologous gene in a model system, runs the risk of missing the many nuances of hypomorphic and/or gain of function variants in the genome of interest.


Assuntos
Neurregulinas/genética , Neurregulinas/fisiologia , Esquizofrenia/genética , Processamento Alternativo , Ligação Genética/genética , Genótipo , Humanos , Neuregulina-1/genética , Neuregulina-1/fisiologia , Neurregulinas/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Esquizofrenia/fisiopatologia
15.
Dev Dyn ; 246(5): 368-380, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28245533

RESUMO

BACKGROUND: Neuromuscular junction (NMJ) development is a multistep process mediated by coordinated interactions between the nerve terminal, target muscle, and perisynaptic Schwann cell that require constant back-and-forth communication. Retrograde and anterograde growth and differentiation factors have been postulated to participate in this communication. While neuregulin1 (NRG1) has been shown to be potent anterograde signal that activates acetylcholine receptor (AChR) transcription and clustering in vitro, its roles in NMJ development in vivo remain elusive. RESULTS: Using the model of chicken embryo, we measured the effects of NRG1 signaling during NMJ development in ovo using quantitative, sequential measures of AChR cluster size and density, pre- and postsynaptic apposition, and the alignment of perisynaptic Schwann cells. Using in ovo electroporation at early stages and a targeted soluble neuregulin antagonist through all developmental stages, we found soluble NRG1 regulates AChR cluster density and size at the earliest stage prior to nerve-AChR cluster contact. Once the nerve contacts with muscle AChRs, NRG1 has pronounced effects on presynaptic specialization and on the alignment of perisynaptic Schwann cells at endplates. CONCLUSION: These findings suggest that, while NRG1 may not be critical for overall development, it appears to be important in fine-tuning pre-, post-, and perisynaptic development of the NMJ. Developmental Dynamics 246:368-380, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Proteínas Aviárias/fisiologia , Músculos/inervação , Neuregulina-1/fisiologia , Junção Neuromuscular/crescimento & desenvolvimento , Animais , Embrião de Galinha , Sinapses Elétricas , Junção Neuromuscular/embriologia , Receptores Colinérgicos/metabolismo , Células de Schwann/citologia , Transdução de Sinais
16.
J Neurosurg ; 127(4): 843-856, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28059646

RESUMO

OBJECTIVE Multiple factors may affect functional recovery after peripheral nerve injury, among them the lesion site and the interval between the injury and the surgical repair. When the nerve segment distal to the lesion site undergoes chronic degeneration, the ensuing regeneration (when allowed) is often poor. The aims of the current study were as follows: 1) to examine the expression changes of the neuregulin 1/ErbB system during long-term nerve degeneration; and 2) to investigate whether a chronically denervated distal nerve stump can sustain nerve regeneration of freshly axotomized axons. METHODS This study used a rat surgical model of delayed nerve repair consisting of a cross suture between the chronically degenerated median nerve distal stump and the freshly axotomized ulnar proximal stump. Before the suture, a segment of long-term degenerated median nerve stump was harvested for analysis. Functional, morphological, morphometric, and biomolecular analyses were performed. RESULTS The results showed that neuregulin 1 is highly downregulated after chronic degeneration, as well as some Schwann cell markers, demonstrating that these cells undergo atrophy, which was also confirmed by ultrastructural analysis. After delayed nerve repair, it was observed that chronic degeneration of the distal nerve stump compromises nerve regeneration in terms of functional recovery, as well as the number and size of regenerated myelinated fibers. Moreover, neuregulin 1 is still downregulated after delayed regeneration. CONCLUSIONS The poor outcome after delayed nerve regeneration might be explained by Schwann cell impairment and the consequent ineffective support for nerve regeneration. Understanding the molecular and biological changes occurring both in the chronically degenerating nerve and in the delayed nerve repair may be useful to the development of new strategies to promote nerve regeneration. The results suggest that neuregulin 1 has an important role in Schwann cell activity after denervation, indicating that its manipulation might be a good strategy for improving outcome after delayed nerve repair.


Assuntos
Regeneração Nervosa , Traumatismos dos Nervos Periféricos/fisiopatologia , Células de Schwann , Animais , Denervação , Feminino , Degeneração Neural , Neuregulina-1/fisiologia , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Fatores de Tempo
17.
J Neurosci ; 36(40): 10285-10295, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27707966

RESUMO

Maturation of excitatory drive onto fast-spiking interneurons (FS INs) in the visual cortex has been implicated in the control of the timing of the critical period for ocular dominance plasticity. However, the mechanisms that regulate the strength of these synapses over cortical development are not understood. Here we use a mouse model to show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 regulate the timing of the critical period. NRG1 enhanced the strength of excitatory synapses onto FS INs, which inhibited ocular dominance plasticity during the critical period but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in postcritical period adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, the strength of excitation onto FS INs is a key determinant of critical period plasticity and is maintained at high levels by NRG-erbB4 signaling to constrain plasticity in adulthood. SIGNIFICANCE STATEMENT: Despite decades of experimentation, the mechanisms by which critical periods of enhanced synaptic plasticity are initiated and terminated are not completely understood. Here we show that neuregulin (NRG) and the receptor tyrosine kinase erbB4 determine critical period timing by controlling the strength of excitatory synapses onto FS INs. NRG1 enhanced excitatory drive onto fast spiking interneurons, which inhibited ocular dominance plasticity in juveniles but rescued plasticity in transgenics with hypoexcitable FS INs. Blocking the effects of endogenous neuregulin via inhibition of erbBs rescued ocular dominance plasticity in adults, allowing recovery from amblyopia induced by chronic monocular deprivation. Thus, in contrast to prevailing views of the termination of the critical period, active maintenance of strong excitation onto FS INs constrains plasticity in adults.


Assuntos
Período Crítico Psicológico , Interneurônios/fisiologia , Neuregulina-1/fisiologia , Córtex Visual/fisiologia , Ambliopia/fisiopatologia , Animais , Dominância Ocular/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuregulina-1/antagonistas & inibidores , Neuregulina-1/genética , Plasticidade Neuronal/fisiologia , Receptor ErbB-4/antagonistas & inibidores , Receptor ErbB-4/genética , Receptor ErbB-4/fisiologia , Recuperação de Função Fisiológica/genética , Sinapses/fisiologia , Visão Monocular/fisiologia , Córtex Visual/citologia
18.
J Neurosci ; 36(40): 10337-10355, 2016 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-27707970

RESUMO

Axon-Schwann cell interactions are crucial for the development, function, and repair of the peripheral nervous system, but mechanisms underlying communication between axons and nonmyelinating Schwann cells are unclear. Here, we show that ER81 is functionally required in a subset of mouse RET+ mechanosensory neurons for formation of Pacinian corpuscles, which are composed of a single myelinated axon and multiple layers of nonmyelinating Schwann cells, and Ret is required for the maintenance of Er81 expression. Interestingly, Er81 mutants have normal myelination but exhibit deficient interactions between axons and corpuscle-forming nonmyelinating Schwann cells. Finally, ablating Neuregulin-1 (Nrg1) in mechanosensory neurons results in no Pacinian corpuscles, and an Nrg1 isoform not required for communication with myelinating Schwann cells is specifically decreased in Er81-null somatosensory neurons. Collectively, our results suggest that a RET-ER81-NRG1 signaling pathway promotes axon communication with nonmyelinating Schwann cells, and that neurons use distinct mechanisms to interact with different types of Schwann cells. SIGNIFICANCE STATEMENT: Communication between neurons and Schwann cells is critical for development, normal function, and regeneration of the peripheral nervous system. Despite many studies about axonal communication with myelinating Schwann cells, mostly via a specific isoform of Neuregulin1, the molecular nature of axonal communication with nonmyelinating Schwann cells is poorly understood. Here, we described a RET-ER81-Neuregulin1 signaling pathway in neurons innervating Pacinian corpuscle somatosensory end organs, which is essential for communication between the innervating axon and the end organ nonmyelinating Schwann cells. We also showed that this signaling pathway uses isoforms of Neuregulin1 that are not involved in myelination, providing evidence that neurons use different isoforms of Neuregulin1 to interact with different types of Schwann cells.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Neuregulina-1/fisiologia , Corpúsculos de Pacini/crescimento & desenvolvimento , Corpúsculos de Pacini/fisiologia , Proteínas Proto-Oncogênicas c-ret/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Animais , Axônios/fisiologia , Proteínas de Ligação a DNA/genética , Mecanotransdução Celular/genética , Mecanotransdução Celular/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Bainha de Mielina/fisiologia , Neuregulina-1/genética , Neurônios/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Proteínas Proto-Oncogênicas c-ret/genética , Células de Schwann/fisiologia , Fatores de Transcrição/genética
19.
Neuron ; 92(1): 160-173, 2016 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-27641496

RESUMO

Experience alters cortical networks through neural plasticity mechanisms. During a developmental critical period, the most dramatic consequence of occluding vision through one eye (monocular deprivation) is a rapid loss of excitatory synaptic inputs to parvalbumin-expressing (PV) inhibitory neurons in visual cortex. Subsequent cortical disinhibition by reduced PV cell activity allows for excitatory ocular dominance plasticity. However, the molecular mechanisms underlying critical period synaptic plasticity are unclear. Here we show that brief monocular deprivation during the critical period downregulates neuregulin-1(NRG1)/ErbB4 signaling in PV neurons, causing retraction of excitatory inputs to PV neurons. Exogenous NRG1 rapidly restores excitatory inputs onto deprived PV cells through downstream PKC-dependent activation and AMPA receptor exocytosis, thus enhancing PV neuronal inhibition to excitatory neurons. NRG1 treatment prevents the loss of deprived eye visual cortical responsiveness in vivo. Our findings reveal molecular, cellular, and circuit mechanisms of NRG1/ErbB4 in regulating the initiation of critical period visual cortical plasticity.


Assuntos
Dominância Ocular/fisiologia , Neuregulina-1/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptor ErbB-4/fisiologia , Córtex Visual/fisiologia , Animais , Período Crítico Psicológico , Regulação para Baixo/fisiologia , Feminino , Masculino , Camundongos , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Neuregulina-1/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Parvalbuminas/metabolismo , Privação Sensorial/fisiologia , Córtex Visual/crescimento & desenvolvimento
20.
Sci Rep ; 6: 31692, 2016 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-27558862

RESUMO

Several lines of evidence suggest that neuregulin 1 (NRG1) signaling may influence cognitive function and neuropathology in Alzheimer's disease (AD). To test this possibility, full-length type I or type III NRG1 was overexpressed via lentiviral vectors in the hippocampus of line 41 AD mouse. Both type I and type III NRG1 improves deficits in the Morris water-maze behavioral task. Neuropathology was also significantly ameliorated. Decreased expression of the neuronal marker MAP2 and synaptic markers PSD95 and synaptophysin in AD mice was significantly reversed. Levels of Aß peptides and plaques were markedly reduced. Furthermore, we showed that soluble ectodomains of both type I and type III NRG1 significantly increased expression of Aß-degrading enzyme neprilysin (NEP) in primary neuronal cultures. Consistent with this finding, immunoreactivity of NEP was increased in the hippocampus of AD mice. These results suggest that NRG1 provides beneficial effects in candidate neuropathologic substrates of AD and, therefore, is a potential target for the treatment of AD.


Assuntos
Doença de Alzheimer/terapia , Neuregulina-1/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Células Cultivadas , Cognição , Feminino , Hipocampo/patologia , Humanos , Aprendizagem em Labirinto , Camundongos Transgênicos , Neprilisina/metabolismo , Ratos
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