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1.
Nat Commun ; 12(1): 2030, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795678

RESUMO

Microglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer's disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer's disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.


Assuntos
Doença de Alzheimer/genética , Modelos Animais de Doenças , Microglia/metabolismo , Plasticidade Neuronal/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Animais , Células Cultivadas , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/citologia , Receptores Imunológicos/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia
2.
Nat Commun ; 12(1): 2421, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33893290

RESUMO

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Mutação , Plasticidade Neuronal/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/genética
3.
Nat Commun ; 12(1): 1932, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33771998

RESUMO

The physical distance between presynaptic Ca2+ channels and the Ca2+ sensors triggering the release of neurotransmitter-containing vesicles regulates short-term plasticity (STP). While STP is highly diversified across synapse types, the computational and behavioral relevance of this diversity remains unclear. In the Drosophila brain, at nanoscale level, we can distinguish distinct coupling distances between Ca2+ channels and the (m)unc13 family priming factors, Unc13A and Unc13B. Importantly, coupling distance defines release components with distinct STP characteristics. Here, we show that while Unc13A and Unc13B both contribute to synaptic signalling, they play distinct roles in neural decoding of olfactory information at excitatory projection neuron (ePN) output synapses. Unc13A clusters closer to Ca2+ channels than Unc13B, specifically promoting fast phasic signal transfer. Reduction of Unc13A in ePNs attenuates responses to both aversive and appetitive stimuli, while reduction of Unc13B provokes a general shift towards appetitive values. Collectively, we provide direct genetic evidence that release components of distinct nanoscopic coupling distances differentially control STP to play distinct roles in neural decoding of sensory information.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Transmissão Sináptica/fisiologia , Animais , Animais Geneticamente Modificados , Comportamento Apetitivo/fisiologia , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Feminino , Interneurônios/metabolismo , Interneurônios/fisiologia , Proteínas de Membrana/genética , Microscopia Confocal , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Interferência de RNA , Sinapses/metabolismo , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismo
4.
J Affect Disord ; 286: 80-86, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33714174

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a serious and common psychiatric disorder with a high prevalence in the population. Although great advances have been made, its pathogenesis is still unclear and a validated biomarker for diagnosis or therapeutic response remains unidentified. This review aims at summarizing the functional role of miRNAs in MDD pathogenesis and their potential as biomarkers for MDD diagnosis and antidepressant response. METHODS: We performed a bibliographic research on the main databases (PubMed, Google Scholar and Web of Science) using the terms "microRNAs", "major depressive disorder", "synaptic plasticity", "biomarker", "antidepressant treatment", in order to find studies that propose the role of microRNAs in MDD pathogenesis and their potential as biomarkers for MDD diagnosis and antidepressant response. RESULTS: microRNAs (miRNAs), a class of small noncoding RNAs, act as key regulators of synaptic plasticity in MDD pathogenesis. Growing researches provide the evidence for peripheral miRNAs as potential biomarkers for MDD diagnosis and antidepressant response. These results suggest that targeting miRNAs directly could be therapeutically beneficial for MDD and miRNAs are potential biomarkers of MDD and its treatment. LIMITATIONS: The role of miRNAs in MDD pathogenesis needs further investigation. Whether miRNAs in peripheral tissues truly represent brain-derived miRNAs is still unclear at the present time. Moreover, only a few blood miRNAs alterations are consistent across studies. CONCLUSIONS: Overall, miRNAs act key regulators of synaptic plasticity in MDD pathogenesis and hold significant promise as biomarkers or therapeutic targets for MDD, but further research is still needed.


Assuntos
Transtorno Depressivo Maior , MicroRNAs , Antidepressivos/uso terapêutico , Biomarcadores , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Humanos , MicroRNAs/genética , Plasticidade Neuronal/genética
5.
Trends Hear ; 25: 23312165211002140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33787399

RESUMO

Genetic biomarkers of neuroplasticity in deaf children treated with cochlear implantation (CI) might facilitate their clinical management, especially giving them better chances of developing proficient spoken language. We investigated whether carrying certain variants of the genes encoding matrix metalloproteinase MMP9 and neurotrophin brain-derived neurotrophic factor (BDNF), involved in synaptic plasticity, can be taken as prognostic markers of how well auditory skills might be acquired. Association analysis of functional MMP9 rs3918242 and BDNF rs6265 variants and the child's auditory development measured at CI activation and 1, 5, 9, 14, and 24 months post CI activation with LittlEARS Questionnaire (LEAQ) was conducted in a group of 100 children diagnosed with DFNB1-related deafness, unilaterally implanted before the age of 2 years. Statistical analysis in the subgroup implanted after 1 year of life (n = 53) showed significant association between MMP9 rs3918242 and LEAQ scores at 1 month (p = .01), at 5 months (p = .01), at 9 months (p = .01), and at 24 months (p = .01) after CI activation. No significant associations in the subgroup implanted before 1 year of life were observed. No significant associations between the BDNF rs6265 and LEAQ score were found. Multiple regression analysis (R2 = .73) in the subgroup implanted after 1 year of life revealed that MMP9 rs3918242 was a significant predictor of treatment outcome. In conclusion, C/C rs3918242 MMP9 predisposes their deaf carriers to better CI outcomes, especially when implanted after the first birthday, than carriers of C/T rs3918242MMP9.


Assuntos
Implante Coclear , Implantes Cocleares , Surdez , Biomarcadores , Fator Neurotrófico Derivado do Encéfalo/genética , Criança , Pré-Escolar , Surdez/diagnóstico , Surdez/genética , Surdez/cirurgia , Humanos , Metaloproteinase 9 da Matriz/genética , Plasticidade Neuronal/genética , Estudos Retrospectivos
6.
J Neurosci ; 41(7): 1401-1417, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33402422

RESUMO

Throughout the nervous system, the convergence of two or more presynaptic inputs on a target cell is commonly observed. The question we ask here is to what extent converging inputs influence each other's structural and functional synaptic plasticity. In complex circuits, isolating individual inputs is difficult because postsynaptic cells can receive thousands of inputs. An ideal model to address this question is the Drosophila larval neuromuscular junction (NMJ) where each postsynaptic muscle cell receives inputs from two glutamatergic types of motor neurons (MNs), known as 1b and 1s MNs. Notably, each muscle is unique and receives input from a different combination of 1b and 1s MNs; we surveyed multiple muscles for this reason. Here, we identified a cell-specific promoter that allows ablation of 1s MNs postinnervation and measured structural and functional responses of convergent 1b NMJs using microscopy and electrophysiology. For all muscles examined in both sexes, ablation of 1s MNs resulted in NMJ expansion and increased spontaneous neurotransmitter release at corresponding 1b NMJs. This demonstrates that 1b NMJs can compensate for the loss of convergent 1s MNs. However, only a subset of 1b NMJs showed compensatory evoked neurotransmission, suggesting target-specific plasticity. Silencing 1s MNs led to similar plasticity at 1b NMJs, suggesting that evoked neurotransmission from 1s MNs contributes to 1b synaptic plasticity. Finally, we genetically blocked 1s innervation in male larvae and robust 1b synaptic plasticity was eliminated, raising the possibility that 1s NMJ formation is required to set up a reference for subsequent synaptic perturbations.SIGNIFICANCE STATEMENT In complex neural circuits, multiple convergent inputs contribute to the activity of the target cell, but whether synaptic plasticity exists among these inputs has not been thoroughly explored. In this study, we examined synaptic plasticity in the structurally and functionally tractable Drosophila larval neuromuscular system. In this convergent circuit, each muscle is innervated by a unique pair of motor neurons. Removal of one neuron after innervation causes the adjacent neuron to increase neuromuscular junction outgrowth and functional output. However, this is not a general feature as each motor neuron differentially compensates. Further, robust compensation requires initial coinnervation by both neurons. Understanding how neurons respond to perturbations in adjacent neurons will provide insight into nervous system plasticity in both healthy and disease states.


Assuntos
Drosophila melanogaster/fisiologia , Junção Neuromuscular/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Técnicas de Inativação de Genes , Larva , Masculino , Neurônios Motores/metabolismo , Músculos/inervação , Músculos/fisiologia , Junção Neuromuscular/genética , Plasticidade Neuronal/genética , Receptores de Glutamato/metabolismo , Transmissão Sináptica
7.
Proc Natl Acad Sci U S A ; 117(40): 25085-25091, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32948689

RESUMO

Hebbian plasticity is a key mechanism for higher brain functions, such as learning and memory. This form of synaptic plasticity primarily involves the regulation of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) abundance and properties, whereby AMPARs are inserted into synapses during long-term potentiation (LTP) or removed during long-term depression (LTD). The molecular mechanisms underlying AMPAR trafficking remain elusive, however. Here we show that glutamate receptor interacting protein 1 (GRIP1), an AMPAR-binding protein shown to regulate the trafficking and synaptic targeting of AMPARs, is required for LTP and learning and memory. GRIP1 is recruited into synapses during LTP, and deletion of Grip1 in neurons blocks synaptic AMPAR accumulation induced by glycine-mediated depolarization. In addition, Grip1 knockout mice exhibit impaired hippocampal LTP, as well as deficits in learning and memory. Mechanistically, we find that phosphorylation of serine-880 of the GluA2 AMPAR subunit (GluA2-S880) is decreased while phosphorylation of tyrosine-876 on GluA2 (GluA2-Y876) is elevated during chemically induced LTP. This enhances the strength of the GRIP1-AMPAR association and, subsequently, the insertion of AMPARs into the postsynaptic membrane. Together, these results demonstrate an essential role of GRIP1 in regulating AMPAR trafficking during synaptic plasticity and learning and memory.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/metabolismo , Receptores de AMPA/genética , Receptores de Glutamato/genética , Animais , Proteínas de Transporte/genética , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Humanos , Aprendizagem/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Fosforilação/genética , Sinapses/genética , Sinapses/metabolismo
8.
Neuron ; 108(1): 128-144.e9, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32810432

RESUMO

Primary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By profiling sensory ganglia at single-cell resolution, we find that all somatosensory neuronal subtypes undergo a similar transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. This transcriptional reprogramming, which is not observed in non-neuronal cells, resolves over a similar time course as target reinnervation and is associated with the restoration of original cell identity. Injury-induced transcriptional reprogramming requires ATF3, a transcription factor that is induced rapidly after injury and necessary for axonal regeneration and functional recovery. Our findings suggest that transcription factors induced early after peripheral nerve injury confer the cellular plasticity required for sensory neurons to transform into a regenerative state.


Assuntos
Fator 3 Ativador da Transcrição/genética , Reprogramação Celular/genética , Gânglios Espinais/citologia , Regulação da Expressão Gênica/genética , Neuralgia/genética , Traumatismos dos Nervos Periféricos/genética , Células Receptoras Sensoriais/metabolismo , Animais , Axônios , Axotomia , Lesões por Esmagamento/genética , Lesões por Esmagamento/metabolismo , Vértebras Lombares , Mecanorreceptores/metabolismo , Camundongos , Regeneração Nervosa , Plasticidade Neuronal/genética , Nociceptores/metabolismo , RNA-Seq , Recuperação de Função Fisiológica , Nervo Isquiático/lesões , Nervo Isquiático/cirurgia , Análise de Célula Única , Nervos Espinhais/lesões , Nervos Espinhais/cirurgia , Transcriptoma
9.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
10.
Nat Commun ; 11(1): 2755, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488011

RESUMO

Fragile X Syndrome results from a loss of Fragile X Mental Retardation Protein (FMRP). We now show that FMRP is a member of a Cav3-Kv4 ion channel complex that is known to regulate A-type potassium current in cerebellar granule cells to produce mossy fiber LTP. Mossy fiber LTP is absent in Fmr1 knockout (KO) mice but is restored by FMRP(1-297)-tat peptide. This peptide further rapidly permeates the blood-brain barrier to enter cells across the cerebellar-cortical axis that restores the balance of protein translation for at least 24 h and transiently reduces elevated levels of activity of adult Fmr1 KO mice in the Open Field Test. These data reveal that FMRP(1-297)-tat can improve function from the levels of protein translation to synaptic efficacy and behaviour in a model of Fragile X syndrome, identifying a potential therapeutic strategy for this genetic disorder.


Assuntos
Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Canais Iônicos/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/patologia , Masculino , Camundongos , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Biossíntese de Proteínas
11.
Nat Commun ; 11(1): 3143, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32561719

RESUMO

Topoisomerase 3ß (Top3ß) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3ß mutations have been linked to schizophrenia, autism, epilepsy, and cognitive impairment. Here we show that Top3ß knockout mice exhibit behavioural phenotypes related to psychiatric disorders and cognitive impairment. The mice also display impairments in hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many with known neuronal functions. Our data suggest that Top3ß is essential for normal brain function, and that defective neuronal activity-dependent transcription may be a mechanism by which Top3ß deletion causes cognitive impairment and psychiatric disorders.


Assuntos
Disfunção Cognitiva/genética , DNA Topoisomerases Tipo I/genética , Transtornos Mentais/genética , Neurogênese/genética , Plasticidade Neuronal/genética , Animais , Técnicas de Observação do Comportamento , Comportamento Animal , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Feminino , Hipocampo/citologia , Hipocampo/diagnóstico por imagem , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/patologia , Camundongos , Camundongos Knockout , Neurônios/patologia , Técnicas Estereotáxicas , Potenciais Sinápticos/genética , Transcrição Genética/fisiologia
12.
J Vis Exp ; (159)2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32478719

RESUMO

Computational modeling of diffusion and reaction of chemical species in a three-dimensional (3D) geometry is a fundamental method to understand the mechanisms of synaptic plasticity in dendritic spines. In this protocol, the detailed 3D structure of the dendrites and dendritic spines is modeled with meshes on the software Blender with CellBlender. The synaptic and extrasynaptic regions are defined on the mesh. Next, the synaptic receptor and synaptic anchor molecules are defined with their diffusion constants. Finally, the chemical reactions between synaptic receptors and synaptic anchors are included and the computational model is solved numerically with the software MCell. This method describes the spatiotemporal path of every single molecule in a 3D geometrical structure. Thus, it is very useful to study the trafficking of synaptic receptors in and out of the dendritic spines during the occurrence of synaptic plasticity. A limitation of this method is that the high number of molecules slows the speed of the simulations. Modeling of dendritic spines with this method allows the study of homosynaptic potentiation and depression within single spines and heterosynaptic plasticity between neighbor dendritic spines.


Assuntos
Espinhas Dendríticas/genética , Plasticidade Neuronal/genética , Humanos , Impressão Tridimensional
13.
PLoS One ; 15(5): e0226790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365120

RESUMO

Patients with DYT1 dystonia caused by the mutated TOR1A gene exhibit risk neutral behaviour compared to controls who are risk averse in the same reinforcement learning task. It is unclear whether this behaviour can be linked to changes in cortico-striatal plasticity demonstrated in animal models which share the same TOR1A mutation. We hypothesised that we could reproduce the experimental risk taking behaviour using a model of the basal ganglia under conditions where cortico-striatal plasticity was abnormal. As dopamine exerts opposing effects on cortico-striatal plasticity via different receptors expressed on medium spiny neurons (MSN) of the direct (D1R dominant, dMSNs) and indirect (D2R dominant, iMSNs) pathways, we tested whether abnormalities in cortico-striatal plasticity in one or both of these pathways could explain the patient's behaviour. Our model could generate simulated behaviour indistinguishable from patients when cortico-striatal plasticity was abnormal in both dMSNs and iMSNs in opposite directions. The risk neutral behaviour of the patients was replicated when increased cortico-striatal long term potentiation in dMSN's was in combination with increased long term depression in iMSN's. This result is consistent with previous observations in rodent models of increased cortico-striatal plasticity at in dMSNs, but contrasts with the pattern reported in vitro of dopamine D2 receptor dependant increases in cortico-striatal LTP and loss of LTD at iMSNs. These results suggest that additional factors in patients who manifest motor symptoms may lead to divergent effects on D2 receptor dependant cortico-striatal plasticity that are not apparent in rodent models of this disease.


Assuntos
Dopamina/genética , Distonia Muscular Deformante/genética , Chaperonas Moleculares/genética , Receptores de Dopamina D2/genética , Animais , Gânglios da Base/metabolismo , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Ciências Biocomportamentais , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopamina/metabolismo , Distonia Muscular Deformante/psicologia , Feminino , Humanos , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Rigidez Muscular/genética , Rigidez Muscular/patologia , Mutação/genética , Vias Neurais/metabolismo , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Reforço Psicológico , Assunção de Riscos , Roedores/genética , Roedores/fisiologia , Sinapses/genética
14.
Neurology ; 94(23): e2404-e2411, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32457210

RESUMO

OBJECTIVE: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD. METHODS: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25). RESULTS: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance. CONCLUSION: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.


Assuntos
Doença de Alzheimer/metabolismo , Apolipoproteínas E/fisiologia , Mitocôndrias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Apolipoproteína E4/genética , Apolipoproteína E4/fisiologia , Química Encefálica , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Mitocôndrias/ultraestrutura , Dinâmica Mitocondrial , Proteínas Mitocondriais/análise , Proteínas do Tecido Nervoso/análise , Plasticidade Neuronal/genética , Biogênese de Organelas , Estresse Oxidativo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/análise , Isoformas de Proteínas/fisiologia , Sirtuína 3/análise , Aprendizagem Verbal
15.
J Neurosci ; 40(27): 5214-5227, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32467358

RESUMO

The limitation of plasticity in the adult brain impedes functional recovery later in life from brain injury or disease. This pressing clinical issue may be resolved by enhancing plasticity in the adult brain. One strategy for triggering robust plasticity in adulthood is to reproduce one of the hallmark physiological events of experience-dependent plasticity observed during the juvenile critical period: to rapidly reduce the activity of parvalbumin (PV)-expressing interneurons and disinhibit local excitatory neurons. This may be achieved through the enhancement of local inhibitory inputs, particularly those of somatostatin (SST)-expressing interneurons. However, to date the means for manipulating SST interneurons for enhancing cortical plasticity in the adult brain are not known. We show that SST interneuron-selective overexpression of Lypd6, an endogenous nicotinic signaling modulator, enhances ocular dominance plasticity in the adult primary visual cortex (V1). Lypd6 overexpression mediates a rapid experience-dependent increase in the visually evoked activity of SST interneurons as well as a simultaneous reduction in PV interneuron activity and disinhibition of excitatory neurons. Recapitulating this transient activation of SST interneurons using chemogenetics similarly enhanced V1 plasticity. Notably, we show that SST-selective Lypd6 overexpression restores visual acuity in amblyopic mice that underwent early long-term monocular deprivation. Our data in both male and female mice reveal selective modulation of SST interneurons and a putative downstream circuit mechanism as an effective method for enhancing experience-dependent cortical plasticity as well as functional recovery in adulthood.SIGNIFICANCE STATEMENT The decline of cortical plasticity after closure of juvenile critical period consolidates neural circuits and behavior, but this limits functional recovery from brain diseases and dysfunctions in later life. Here we show that activation of cortical somatostatin (SST) interneurons by Lypd6, an endogenous modulator of nicotinic acetylcholine receptors, enhances experience-dependent plasticity and recovery from amblyopia in adulthood. This manipulation triggers rapid reduction of PV interneuron activity and disinhibition of excitatory neurons, which are known hallmarks of cortical plasticity during juvenile critical periods. Our study demonstrates modulation of SST interneurons by Lypd6 to achieve robust levels of cortical plasticity in the adult brain and may provide promising targets for restoring brain function in the event of brain trauma or disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Ligadas por GPI/fisiologia , Interneurônios/fisiologia , Plasticidade Neuronal/fisiologia , Somatostatina/fisiologia , Córtex Visual/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Dominância Ocular/genética , Potenciais Evocados Visuais/genética , Potenciais Evocados Visuais/fisiologia , Feminino , Proteínas Ligadas por GPI/genética , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Plasticidade Neuronal/genética , Fosfatidilinositóis/farmacologia , Receptores Nicotínicos/genética , Recuperação de Função Fisiológica/genética , Visão Monocular/genética , Visão Monocular/fisiologia , Acuidade Visual/genética
16.
Am J Physiol Regul Integr Comp Physiol ; 318(6): R1058-R1067, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32348679

RESUMO

Circadian rhythms are endogenous and entrainable daily patterns of physiology and behavior. Molecular mechanisms underlie circadian rhythms, characterized by an ~24-h pattern of gene expression of core clock genes. Although it has long been known that breathing exhibits circadian rhythms, little is known concerning clock gene expression in any element of the neuromuscular system controlling breathing. Furthermore, we know little concerning gene expression necessary for specific respiratory functions, such as phrenic motor plasticity. Thus, we tested the hypotheses that transcripts for clock genes (Bmal1, Clock, Per1, and Per2) and molecules necessary for phrenic motor plasticity (Htr2a, Htr2b, Bdnf, and Ntrk2) oscillate in regions critical for phrenic/diaphragm motor function via RT-PCR. Tissues were collected from male Sprague-Dawley rats entrained to a 12-h light-dark cycle at 4 zeitgeber times (ZT; n = 8 rats/group): ZT5, ZT11, ZT17, and ZT23; ZT0 = lights on. Here, we demonstrate that 1) circadian clock genes (Bmal1, Clock, Per1, and Per2) oscillate in regions critical for phrenic/diaphragm function, including the caudal medulla, ventral C3-C5 cervical spinal cord, and diaphragm; 2) the clock protein BMAL1 is localized within CtB-labeled phrenic motor neurons; 3) genes necessary for intermittent hypoxia-induced phrenic/diaphragm motor plasticity (Htr2b and Bdnf) oscillate in the caudal medulla and ventral C3-C5 spinal cord; and 4) there is higher intensity of immunofluorescent BDNF protein within phrenic motor neurons at ZT23 compared with ZT11 (n = 11 rats/group). These results suggest local circadian clocks exist in the phrenic motor system and confirm the potential for local circadian regulation of neuroplasticity and other elements of the neural network controlling breathing.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano/fisiologia , Neurônios Motores/metabolismo , Plasticidade Neuronal/genética , Nervo Frênico/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Expressão Gênica , Masculino , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo
17.
Neuron ; 106(5): 769-777.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32199104

RESUMO

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.


Assuntos
Homeostase/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Córtex Visual/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Autístico/genética , Comportamento Animal/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Asseio Animal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos de Lítio/farmacologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Córtex Visual/citologia , Córtex Visual/metabolismo
18.
Proc Natl Acad Sci U S A ; 117(10): 5502-5509, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32098843

RESUMO

The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein Gαo1 to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.


Assuntos
Habenula/fisiologia , Plasticidade Neuronal/fisiologia , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Receptores Acoplados a Proteínas-G/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Células CHO , Cricetulus , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Habenula/metabolismo , Humanos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Acoplados a Proteínas-G/genética , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia
19.
Epilepsia ; 61(3): 549-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32096222

RESUMO

OBJECTIVE: To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease-modifying activity of the 5HT2 receptor agonist fenfluramine. METHODS: We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage-gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single-cell RNA-Seq, morphometric analysis of transgenic reporter-labeled γ-aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. RESULTS: Homozygous mutant (scn1labmut/mut ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20-minute recording; P < .0001; one-way analysis of variance). Drop-Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. SIGNIFICANCE: Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first-time evidence for potential disease modification by fenfluramine.


Assuntos
Encéfalo/fisiopatologia , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Plasticidade Neuronal/genética , Proteínas de Peixe-Zebra/genética , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas , Proliferação de Células/efeitos dos fármacos , Diazepam/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Epilepsias Mioclônicas/fisiopatologia , Fenfluramina/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Perfilação da Expressão Gênica , Gliose/genética , Gliose/patologia , Locomoção/efeitos dos fármacos , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Análise de Célula Única , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
20.
PLoS Genet ; 16(2): e1008626, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32059017

RESUMO

Neuronal pruning is a commonly observed phenomenon for the developing nervous systems to ensure precise wiring of neural circuits. The function of Ik2 kinase and its downstream mediator, Spindle-F (Spn-F), are essential for dendrite pruning of Drosophila sensory neurons during development. However, little is known about how Ik2/Spn-F signaling is transduced in neurons and ultimately results in dendrite pruning. Our genetic analyses and rescue experiments demonstrated that the small GTPase Rab11, especially the active GTP-bound form, is required for dendrite pruning. We also found that Rab11 shows genetic interactions with spn-F and ik2 on pruning. Live imaging of single neurons and antibody staining reveal normal Ik2 kinase activation in Rab11 mutant neurons, suggesting that Rab11 could have a functional connection downstream of and/or parallel to the Ik2 kinase signaling. Moreover, we provide biochemical evidence that both the Ik2 kinase activity and the formation of Ik2/Spn-F/Rab11 complexes are central to promote Rab11 activation in cells. Together, our studies reveal that a critical role of Ik2/Spn-F signaling in neuronal pruning is to promote Rab11 activation, which is crucial for dendrite pruning in neurons.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Quinase I-kappa B/metabolismo , Plasticidade Neuronal/genética , Células Receptoras Sensoriais/fisiologia , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Animais Geneticamente Modificados , Linhagem Celular , Dendritos/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Embrião não Mamífero , Técnicas de Silenciamento de Genes , Microscopia Intravital , Proteínas Associadas aos Microtúbulos/metabolismo , Células Receptoras Sensoriais/citologia , Transdução de Sinais/fisiologia , Imagem com Lapso de Tempo , Proteínas rab de Ligação ao GTP/genética
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