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1.
bioRxiv ; 2024 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-38979341

RESUMO

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes. We generated a conditional KO (cKO) of Smad4 in astrocytes to suppress BMP signaling, and found this lessens audiogenic seizure severity in FXS mice. To ask how this occurs on a molecular level, we performed in vivo transcriptomic and proteomic profiling of cortical astrocytes, finding upregulation of metabolic pathways, and downregulation of secretory machinery and secreted proteins in FXS astrocytes, with these alterations no longer present when BMP signaling is suppressed. Functionally, astrocyte Smad4 cKO restores deficits in inhibitory synapses present in FXS auditory cortex. Thus, astrocytes contribute to FXS molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.

2.
bioRxiv ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38559139

RESUMO

Neural circuits in many brain regions are refined by experience. Sensory circuits support higher plasticity at younger ages during critical periods - times of circuit refinement and maturation - and limit plasticity in adulthood for circuit stability. The mechanisms underlying these differing plasticity levels and how they serve to maintain and stabilize the properties of sensory circuits remain largely unclear. By combining a transcriptomic approach with ex vivo electrophysiology and in vivo imaging techniques, we identify that astrocytes release cellular communication network factor 1 (CCN1) to maintain synapse and circuit stability in the visual cortex. By overexpressing CCN1 in critical period astrocytes, we find that it promotes the maturation of inhibitory circuits and limits ocular dominance plasticity. Conversely, by knocking out astrocyte CCN1 in adults, binocular circuits are destabilized. These studies establish CCN1 as a novel astrocyte-secreted factor that stabilizes neuronal circuits. Moreover, they demonstrate that the composition and properties of sensory circuits require ongoing maintenance in adulthood, and that these maintenance cues are provided by astrocytes.

3.
Artigo em Inglês | MEDLINE | ID: mdl-38346858

RESUMO

Astrocytes play an integral role in the development, maturation, and refinement of neuronal circuits. Astrocytes secrete proteins and lipids that instruct the formation of new synapses and induce the maturation of existing synapses. Through contact-mediated signaling, astrocytes can regulate the formation and state of synapses within their domain. Through phagocytosis, astrocytes participate in the elimination of excess synaptic connections. In this work, we will review key findings on the molecular mechanisms of astrocyte-synapse interaction with a focus on astrocyte-secreted factors, contact-mediated mechanisms, and synapse elimination. We will discuss this in the context of typical brain development and maintenance, as well as consider the consequences of dysfunction in these pathways in neurological disorders, highlighting a role for astrocytes in health and disease.

4.
bioRxiv ; 2023 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-37808668

RESUMO

Neuronal dendrite patterning and synapse formation are tightly regulated during development to promote proper connectivity. Astrocyte-secreted proteins act as guidance and pro-synaptogenic factors during development, but little is known about how astrocytes may contribute to neurodevelopmental disorders. Here we identify down-regulation of the astrocyte-secreted molecule pleiotrophin as a major contributor to neuronal morphological alterations in the Ts65Dn mouse model of Down Syndrome. We find overlapping deficits in neuronal dendrites, spines and intracortical synapses in Ts65Dn mutant and pleiotrophin knockout mice. By targeting pleiotrophin overexpression to astrocytes in adult Ts65Dn mutant mice in vivo , we show that pleiotrophin can rescue dendrite morphology and spine density and increase excitatory synapse number. We further demonstrate functional improvements in behavior. Our findings identify pleiotrophin as a molecule that can be used in Down Syndrome to promote proper circuit connectivity, importantly at later stages of development after typical periods of circuit refinement have completed.

5.
STAR Protoc ; 4(4): 102599, 2023 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-37742178

RESUMO

Astrocytes are glial cells of the central nervous system that modulate neuronal function. Here, we present glyoxal-fixed astrocyte nuclei transcriptomics (GFAT), a protocol for the purification and transcriptomic analysis of astrocyte nuclei from the cortex and cerebellum of adult and aged fresh mouse brain. We describe steps for tissue dissection, glyoxal fixation, homogenization, nuclei isolation, antibody staining, fluorescence-activated cell sorting, and RT-qPCR or bulk RNA sequencing. GFAT does not require transgenic lines or viral injection and allows parallel astrocyte and neuron profiling.


Assuntos
Astrócitos , Núcleo Celular , Camundongos , Animais , Astrócitos/metabolismo , Núcleo Celular/metabolismo , Neuroglia , Perfilação da Expressão Gênica/métodos , Glioxal/metabolismo
6.
Nat Chem Biol ; 19(2): 187-197, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36266352

RESUMO

Lipids contribute to the structure, development, and function of healthy brains. Dysregulated lipid metabolism is linked to aging and diseased brains. However, our understanding of lipid metabolism in aging brains remains limited. Here we examined the brain lipidome of mice across their lifespan using untargeted lipidomics. Co-expression network analysis highlighted a progressive decrease in 3-sulfogalactosyl diacylglycerols (SGDGs) and SGDG pathway members, including the potential degradation products lyso-SGDGs. SGDGs show an age-related decline specifically in the central nervous system and are associated with myelination. We also found that an SGDG dramatically suppresses LPS-induced gene expression and release of pro-inflammatory cytokines from macrophages and microglia by acting on the NF-κB pathway. The detection of SGDGs in human and macaque brains establishes their evolutionary conservation. This work enhances interest in SGDGs regarding their roles in aging and inflammatory diseases and highlights the complexity of the brain lipidome and potential biological functions in aging.


Assuntos
Envelhecimento , Lipídeos , Animais , Humanos , Camundongos , Envelhecimento/genética , Anti-Inflamatórios , Encéfalo/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo
7.
Nat Rev Neurosci ; 24(1): 23-39, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36316501

RESUMO

There is increasing appreciation that non-neuronal cells contribute to the initiation, progression and pathology of diverse neurodegenerative disorders. This Review focuses on the role of astrocytes in disorders including Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis. The important roles astrocytes have in supporting neuronal function in the healthy brain are considered, along with studies that have demonstrated how the physiological properties of astrocytes are altered in neurodegenerative disorders and may explain their contribution to neurodegeneration. Further, the question of whether in neurodegenerative disorders with specific genetic mutations these mutations directly impact on astrocyte function, and may suggest a driving role for astrocytes in disease initiation, is discussed. A summary of how astrocyte transcriptomic and proteomic signatures are altered during the progression of neurodegenerative disorders and may relate to functional changes is provided. Given the central role of astrocytes in neurodegenerative disorders, potential strategies to target these cells for future therapeutic avenues are discussed.


Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Humanos , Astrócitos/fisiologia , Proteômica , Doenças Neurodegenerativas/patologia , Esclerose Lateral Amiotrófica/patologia , Neurônios/patologia
8.
Nat Neurosci ; 25(9): 1163-1178, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36042312

RESUMO

Astrocytes negatively impact neuronal development in many models of neurodevelopmental disorders (NDs); however, how they do this, and if mechanisms are shared across disorders, is not known. In this study, we developed a cell culture system to ask how astrocyte protein secretion and gene expression change in three mouse models of genetic NDs (Rett, Fragile X and Down syndromes). ND astrocytes increase release of Igfbp2, a secreted inhibitor of insulin-like growth factor (IGF). IGF rescues neuronal deficits in many NDs, and we found that blocking Igfbp2 partially rescues inhibitory effects of Rett syndrome astrocytes, suggesting that increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified that increased BMP signaling is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X and Rett syndrome astrocytes reverses inhibitory effects on neurite outgrowth. This work provides a resource of astrocyte-secreted proteins in health and ND models and identifies novel targets for intervention in diverse NDs.


Assuntos
Transtornos do Neurodesenvolvimento , Síndrome de Rett , Animais , Astrócitos/metabolismo , Camundongos , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/metabolismo , Neurogênese , Neurônios/metabolismo , Síndrome de Rett/metabolismo
9.
Sci Rep ; 12(1): 4176, 2022 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-35264691

RESUMO

Ischemic injury occurs when the brain is deprived of blood flow, preventing cells from receiving essential nutrients. The injury core is the brain region directly deprived and is surrounded by the peri-infarct area, the region with recovery potential. In the peri-infarct area neurons undergo acute loss of dendritic spines, which modifies synaptic plasticity and determines neuronal survival. Astrocytes can be protective or detrimental to the ischemic injury response depending on the specific stage, yet we lack clear understanding of the underlying mechanisms. Chordin-like 1 (Chrdl1) is an astrocyte-secreted protein that promotes synaptic maturation and limits experience-dependent plasticity in the mouse visual cortex. Given this plasticity-limiting function we asked if Chrdl1 regulates the response to ischemic injury, modelled using photothrombosis (PT). We find that Chrdl1 mRNA is upregulated in astrocytes in the peri-infarct area in both acute and sub-acute phases post-PT. To determine the impact of increased Chrdl1 on the response to PT we analyzed Chrdl1 knock-out mice. We find that absence of Chrdl1 prevents ischemia-induced spine loss in the peri-infarct area and reduces cell death in the core, without impacting gliosis. These findings highlight the important role of astrocyte-secreted proteins in regulating structural plasticity in response to brain ischemic injuries.


Assuntos
Lesões Encefálicas , Isquemia Encefálica , Animais , Astrócitos/metabolismo , Lesões Encefálicas/metabolismo , Isquemia Encefálica/metabolismo , Proteínas do Olho/metabolismo , Glicoproteínas , Infarto , Peptídeos e Proteínas de Sinalização Intercelular , Isquemia/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
11.
Elife ; 102021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34494546

RESUMO

Astrocytes regulate the formation and function of neuronal synapses via multiple signals; however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development is also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single-nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.


Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Sinapses/metabolismo , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento/genética , Neurônios/metabolismo , Terminações Pré-Sinápticas/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/genética , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/metabolismo
12.
Nature ; 592(7854): 360-361, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33828277
13.
Nat Neurosci ; 24(3): 312-325, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589835

RESUMO

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.


Assuntos
Envelhecimento/patologia , Astrócitos/patologia , Encéfalo/patologia , Medula Espinal/patologia , Animais , Encefalopatias/patologia , Lesões Encefálicas/patologia , Humanos , Traumatismos da Medula Espinal/patologia
14.
Neurosci Res ; 167: 17-29, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33316304

RESUMO

Glial cells are non-neuronal cells in the nervous system that are crucial for proper brain development and function. Three major classes of glia in the central nervous system (CNS) include astrocytes, microglia and oligodendrocytes. These cells have dynamic morphological and functional properties and constantly surveil neural activity throughout life, sculpting synaptic plasticity. Astrocytes form part of the tripartite synapse with neurons and perform many homeostatic functions essential to proper synaptic function including clearing neurotransmitter and regulating ion balance; they can modify these properties, in addition to additional mechanisms such as gliotransmitter release, to influence short- and long-term plasticity. Microglia, the resident macrophage of the CNS, monitor synaptic activity and can eliminate synapses by phagocytosis or modify synapses by release of cytokines or neurotrophic factors. Oligodendrocytes regulate speed of action potential conduction and efficiency of information exchange through the formation of myelin, having important consequences for the plasticity of neural circuits. A deeper understanding of how glia modulate synaptic and circuit plasticity will further our understanding of the ongoing changes that take place throughout life in the dynamic environment of the CNS.


Assuntos
Neuroglia , Plasticidade Neuronal , Astrócitos , Neurônios , Sinapses , Transmissão Sináptica
15.
Front Neural Circuits ; 15: 786293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35069124

RESUMO

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.


Assuntos
Astrócitos , Sinapses , Animais , Camundongos , Neurogênese , Neurônios , Optogenética
16.
Neurobiol Dis ; 143: 105008, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32622920

RESUMO

Aging is the strongest risk factor for metabolic, vascular and neurodegenerative diseases. Aging alone is associated with a gradual decline of cognitive and motor functions. Considering an increasing elderly population in the last century, understanding the cellular and molecular mechanisms contributing to brain aging is of vital importance. Recent genetic and transcriptomic findings strongly suggest that glia are the first cells changing with aging. Glial cells constitute around 50% of the total cells in the brain and play key roles regulating brain homeostasis in health and disease. Their essential functions include providing nutritional support to neurons, activation of immune responses, and regulation of synaptic transmission and plasticity. In this review we discuss how glia are altered in the aging brain and whether these alterations are protective or contribute to the age-related pathological cascade. We focus on the major morphological, transcriptional and functional changes affecting glia in a range of systems, including human, non-human primates, and rodents. We also highlight future directions for investigating the roles of glia in brain aging.


Assuntos
Envelhecimento/patologia , Encéfalo/patologia , Neuroglia/patologia , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Neuroglia/metabolismo
18.
Cell ; 177(5): 1091-1093, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100265

RESUMO

Are neurons solely responsible for determining behavioral output, or can other brain cells modulate behavior? In this issue of Cell, Nagai et al. demonstrate that striatal astrocytes, through GABAB receptor signaling, regulate behaviors including hyperactivity and attention by inducing new synapse formation between neurons.


Assuntos
Astrócitos , Sinais (Psicologia) , Atenção , Neurônios , Receptores de GABA-B
19.
Am J Hum Genet ; 104(5): 914-924, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982611

RESUMO

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.


Assuntos
Surdez/congênito , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Variação Genética , Glipicanas/genética , Deformidades Congênitas das Extremidades Inferiores/genética , Deformidades Congênitas das Extremidades Inferiores/patologia , Adulto , Criança , Pré-Escolar , Surdez/genética , Surdez/patologia , Feminino , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Adulto Jovem
20.
Science ; 362(6411): 181-185, 2018 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-30309945

RESUMO

Glia constitute roughly half of the cells of the central nervous system (CNS) but were long-considered to be static bystanders to its formation and function. Here we provide an overview of how the diverse and dynamic functions of glial cells orchestrate essentially all aspects of nervous system formation and function. Radial glia, astrocytes, oligodendrocyte progenitor cells, oligodendrocytes, and microglia each influence nervous system development, from neuronal birth, migration, axon specification, and growth through circuit assembly and synaptogenesis. As neural circuits mature, distinct glia fulfill key roles in synaptic communication, plasticity, homeostasis, and network-level activity through dynamic monitoring and alteration of CNS structure and function. Continued elucidation of glial cell biology, and the dynamic interactions of neurons and glia, will enrich our understanding of nervous system formation, health, and function.


Assuntos
Sistema Nervoso Central/citologia , Sistema Nervoso Central/embriologia , Neuroglia/fisiologia , Animais , Movimento Celular , Sistema Nervoso Central/irrigação sanguínea , Camundongos , Neurogênese , Neuroglia/citologia , Plasticidade Neuronal , Neurônios/citologia , Neurônios/fisiologia , Sinapses , Transmissão Sináptica
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