scholarly journals Possible Involvement of TLRs and Hemichannels in Stress-Induced CNS Dysfunction via Mastocytes, and Glia Activation

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Adam Aguirre ◽  
Carola J. Maturana ◽  
Paloma A. Harcha ◽  
Juan C. Sáez
Keyword(s):  
Glial Cells ◽  
Neuronal Development ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Atp Release ◽  
Autism Spectrum ◽  
Membrane Pores ◽  
The Central Nervous System ◽  
Cns Dysfunction

In the central nervous system (CNS), mastocytes and glial cells (microglia, astrocytes and oligodendrocytes) function as sensors of neuroinflammatory conditions, responding to stress triggers or becoming sensitized to subsequent proinflammatory challenges. The corticotropin-releasing hormone and glucocorticoids are critical players in stress-induced mastocyte degranulation and potentiation of glial inflammatory responses, respectively. Mastocytes and glial cells express different toll-like receptor (TLR) family members, and their activation via proinflammatory molecules can increase the expression of connexin hemichannels and pannexin channels in glial cells. These membrane pores are oligohexamers of the corresponding protein subunits located in the cell surface. They allow ATP release and Ca2+influx, which are two important elements of inflammation. Consequently, activated microglia and astrocytes release ATP and glutamate, affecting myelinization, neuronal development, and survival. Binding of ligands to TLRs induces a cascade of intracellular events leading to activation of several transcription factors that regulate the expression of many genes involved in inflammation. During pregnancy, the previous responses promoted by viral infections and other proinflammatory conditions are common and might predispose the offspring to develop psychiatric disorders and neurological diseases. Such disorders could eventually be potentiated by stress and might be part of the etiopathogenesis of CNS dysfunctions including autism spectrum disorders and schizophrenia.

scholarly journals Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model

2019 ◽  
Vol 20 (9) ◽  
pp. 2134 ◽  
Author(s):  
Ann Katrin Sauer ◽  
Juergen Bockmann ◽  
Konrad Steinestel ◽  
Tobias M. Boeckers ◽  
Andreas M. Grabrucker
Keyword(s):  
Autism Spectrum Disorders ◽  
Inflammatory Responses ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Intestinal Morphology ◽  
Microbiota Composition ◽  
Knock Out ◽  
E Coli ◽  
The Central Nervous System ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in Shank3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of Shank3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of Shank3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in Shank3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms.

scholarly journals Neuroglial ATP release through innexin channels controls microglial cell movement to a nerve injury

2010 ◽  
Vol 136 (4) ◽  
pp. 425-442 ◽  
Author(s):  
Stuart E. Samuels ◽  
Jeffrey B. Lipitz ◽  
Gerhard Dahl ◽  
Kenneth J. Muller
Keyword(s):  
Glial Cell ◽  
Nerve Injury ◽  
Glial Cells ◽  
Cell Injury ◽  
Atp Release ◽  
Cell Movement ◽  
Calcium Wave ◽  
Directed Movement ◽  
The Central Nervous System ◽  
Microglial Migration

Microglia, the immune cells of the central nervous system, are attracted to sites of injury. The injury releases adenosine triphosphate (ATP) into the extracellular space, activating the microglia, but the full mechanism of release is not known. In glial cells, a family of physiologically regulated unpaired gap junction channels called innexons (invertebrates) or pannexons (vertebrates) located in the cell membrane is permeable to ATP. Innexons, but not pannexons, also pair to make gap junctions. Glial calcium waves, triggered by injury or mechanical stimulation, open pannexon/innexon channels and cause the release of ATP. It has been hypothesized that a glial calcium wave that triggers the release of ATP causes rapid microglial migration to distant lesions. In the present study in the leech, in which a single giant glial cell ensheathes each connective, hydrolysis of ATP with 10 U/ml apyrase or block of innexons with 10 µM carbenoxolone (CBX), which decreased injury-induced ATP release, reduced both movement of microglia and their accumulation at lesions. Directed movement and accumulation were restored in CBX by adding ATP, consistent with separate actions of ATP and nitric oxide, which is required for directed movement but does not activate glia. Injection of glia with innexin2 (Hminx2) RNAi inhibited release of carboxyfluorescein dye and microglial migration, whereas injection of innexin1 (Hminx1) RNAi did not when measured 2 days after injection, indicating that glial cells’ ATP release through innexons was required for microglial migration after nerve injury. Focal stimulation either mechanically or with ATP generated a calcium wave in the glial cell; injury caused a large, persistent intracellular calcium response. Neither the calcium wave nor the persistent response required ATP or its release. Thus, in the leech, innexin membrane channels releasing ATP from glia are required for migration and accumulation of microglia after nerve injury.

scholarly journals Intrauterine Viral Infections: Impact of Inflammation on Fetal Neurodevelopment

2021 ◽  
Vol 15 ◽  
Author(s):  
Sourav Ganguli ◽  
Pavithra L. Chavali
Keyword(s):  
Neurodevelopmental Disorders ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Fetal Brain ◽  
Preterm Births ◽  
Autism Spectrum ◽  
Future Research ◽  
Increased Risk ◽  
Mechanistic Basis ◽  
Simplex Virus

Intrauterine viral infections during pregnancy by pathogens such as Zika virus, Cytomegalovirus, Rubella and Herpes Simplex virus can lead to prenatal as well as postnatal neurodevelopmental disorders. Although maternal viral infections are common during pregnancy, viruses rarely penetrate the trophoblast. When they do cross, viruses can cause adverse congenital health conditions for the fetus. In this context, maternal inflammatory responses to these neurotropic pathogens play a significant role in negatively affecting neurodevelopment. For instance, intrauterine inflammation poses an increased risk of neurodevelopmental disorders such as microcephaly, schizophrenia, autism spectrum disorder, cerebral palsy and epilepsy. Severe inflammatory responses have been linked to stillbirths, preterm births, abortions and microcephaly. In this review, we discuss the mechanistic basis of how immune system shapes the landscape of the brain and how different neurotropic viral pathogens evoke inflammatory responses. Finally, we list the consequences of neuroinflammation on fetal brain development and discuss directions for future research and intervention strategies.

scholarly journals An Update of Palmitoylethanolamide and Luteolin Effects in Preclinical and Clinical Studies of Neuroinflammatory Events

Antioxidants ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 216 ◽  
Author(s):  
Marika Cordaro ◽  
Salvatore Cuzzocrea ◽  
Rosalia Crupi
Keyword(s):  
Nervous System ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
Monocytes And Macrophages ◽  
Central Nervous Systems ◽  
The Central Nervous System ◽  
Spectrum Disorders ◽  
Dynamic Series ◽  
Preclinical And Clinical Studies

The inflammation process represents of a dynamic series of phenomena that manifest themselves with an intense vascular reaction. Neuroinflammation is a reply from the central nervous system (CNS) and the peripheral nervous system (PNS) to a changed homeostasis. There are two cell systems that mediate this process: the glia of the CNS and the lymphocites, monocytes, and macrophages of the hematopoietic system. In both the peripheral and central nervous systems, neuroinflammation plays an important role in the pathogenesis of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, and in neuropsychiatric illnesses, such as depression and autism spectrum disorders. The resolution of neuroinflammation is a process that allows for inflamed tissues to return to homeostasis. In this process the important players are represented by lipid mediators. Among the naturally occurring lipid signaling molecules, a prominent role is played by the N-acylethanolamines, namely N-arachidonoylethanolamine and its congener N-palmitoylethanolamine, which is also named palmitoylethanolamide or PEA. PEA possesses a powerful neuroprotective and anti-inflammatory power but has no antioxidant effects per se. For this reason, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treating neuroinflammation. The aim of this review is to discuss the role of ultramicronized PEA and co-ultramicronized PEA with luteolin in several neurological diseases using preclinical and clinical approaches.

scholarly journals The Epigenome in Neurodevelopmental Disorders

2021 ◽  
Vol 15 ◽  
Author(s):  
Julia Reichard ◽  
Geraldine Zimmer-Bensch
Keyword(s):  
Cortical Neurons ◽  
Neuronal Development ◽  
Psychiatric Symptoms ◽  
Autism Spectrum ◽  
Epigenetic Mechanisms ◽  
Functional Deficits ◽  
The Central Nervous System ◽  
Genetic And Environmental Factors ◽  
Higher Cognitive Functions ◽  
External Stimuli

Neurodevelopmental diseases (NDDs), such as autism spectrum disorders, epilepsy, and schizophrenia, are characterized by diverse facets of neurological and psychiatric symptoms, differing in etiology, onset and severity. Such symptoms include mental delay, cognitive and language impairments, or restrictions to adaptive and social behavior. Nevertheless, all have in common that critical milestones of brain development are disrupted, leading to functional deficits of the central nervous system and clinical manifestation in child- or adulthood. To approach how the different development-associated neuropathologies can occur and which risk factors or critical processes are involved in provoking higher susceptibility for such diseases, a detailed understanding of the mechanisms underlying proper brain formation is required. NDDs rely on deficits in neuronal identity, proportion or function, whereby a defective development of the cerebral cortex, the seat of higher cognitive functions, is implicated in numerous disorders. Such deficits can be provoked by genetic and environmental factors during corticogenesis. Thereby, epigenetic mechanisms can act as an interface between external stimuli and the genome, since they are known to be responsive to external stimuli also in cortical neurons. In line with that, DNA methylation, histone modifications/variants, ATP-dependent chromatin remodeling, as well as regulatory non-coding RNAs regulate diverse aspects of neuronal development, and alterations in epigenomic marks have been associated with NDDs of varying phenotypes. Here, we provide an overview of essential steps of mammalian corticogenesis, and discuss the role of epigenetic mechanisms assumed to contribute to pathophysiological aspects of NDDs, when being disrupted.

scholarly journals Cholesterol in autism spectrum disorders

2021 ◽  
Author(s):  
Rafael Franco ◽  
Rafael Rivas-Santisteban ◽  
Gemma Navarro ◽  
Irene Reyes-Resina
Keyword(s):  
Autism Spectrum Disorders ◽  
Neural Development ◽  
Developmental Stages ◽  
Neurological Diseases ◽  
Autism Spectrum ◽  
New Therapeutic Approaches ◽  
Degree Of Disability ◽  
The Central Nervous System ◽  
Spectrum Disorders ◽  
The Look

The autism spectrum disorder (ASD) comprises a series of neurological diseases that share serious alterations of the development of the central nervous system. The degree of disability may vary so that Asperger’s may have a relatively normal life and get positions of responsibility in corporations and even in Governments, whereas other ASD sufferers are fully dependent on caregivers and have serious cognitive deficits. Although the first cases of autism were detected by looking at failures in metabolism, e.g., phenylketonuria, to later identify the faulty gene, today the trend is the opposite, first obtaining the exome and minimizing the look for altered parameters in blood, urine, etc. Cholesterol is key for neural development as it is not able to cross the blood brain barrier. Therefore, any gene or environmental factor that affects cholesterol synthesis will impact early developmental stages eventually leading to a disease within the autism spectrum and/or schizophrenia. This review provides data of the relevance of cholesterol dyshomeostasis in autism spectrum disorders. Determining biochemical parameters in body fluids should help to provide new therapeutic approaches in some cases of autism.

Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action

1992 ◽  
Vol 263 (1) ◽  
pp. C1-C16 ◽  
Author(s):  
E. N. Benveniste
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Glial Cells ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Lymphoid Cells ◽  
Disease States ◽  
Activated T Lymphocytes ◽  
The Central Nervous System ◽  
And Function

In recent years, there has been increasing evidence that soluble mediators such as cytokines from activated T lymphocytes and macrophages are able to modulate the growth and function of cells found within the central nervous system (CNS), specifically macroglia and microglia cells. Furthermore, glial cells, upon activation, can secrete immunoregulatory factors that influence lymphoid/mononuclear cells as well as the glial cells themselves. Thus the potential exists for bidirectional communication between lymphoid cells and glial cells within the CNS, which in part is mediated via cytokines. This review describes various neurological disease states in which both immune and glial cells may contribute to inflammation and immunologic events occurring in the CNS. The mechanisms by which glial cells both respond to and synthesize a variety of cytokines within the CNS and the capacity of glial cells to acquire major histocompatibility complex antigens and function as antigen-presenting cells within the CNS are described in detail. The implications of these functions, cytokine secretion and antigen presentation, by glial cells are discussed with respect to neurological diseases associated with autoimmunity and/or inflammation.

Respiratory viral infections and associated neurological manifestations

Neuroforum ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shirin Hosseini ◽  
Kristin Michaelsen-Preusse ◽  
Martin Korte
Keyword(s):  
Viral Infections ◽  
Neurological Diseases ◽  
Animal Health ◽  
Respiratory Viruses ◽  
Target Tissue ◽  
Direct Invasion ◽  
Spanish Flu ◽  
The Central Nervous System ◽  
Respiratory Viral Infections ◽  
The Brain

Abstract Respiratory viruses as a major threat to human and animal health today are still a leading cause of worldwide severe pandemics. Although the primary target tissue of these viruses is the lung, they can induce immediate or delayed neuropathological manifestations in humans and animals. Already after the Spanish flu (1918/20) evidence accumulated that neurological diseases can be induced by respiratory viral infections as some patients showed parkinsonism, seizures, or dementia. In the recent outbreak of COVID-19 as well patients suffered from headache, dizziness, nausea, or reduced sense of smell and taste suggesting that SARS-CoV2 may affect the central nervous system (CNS). It was shown that different respiratory viral infections can lead to deleterious complications in the CNS by a direct invasion of the virus into the brain and/or indirect pathways via proinflammatory cytokine expression. Therefore, we will discuss in this review mechanisms how the most prevalent respiratory viruses including influenza and coronaviruses in humans can exert long-lasting detrimental effects on the CNS and possible links to the development of neurodegenerative diseases as an enduring consequence.

scholarly journals Commissural axon guidance in the developing spinal cord: from Cajal to the present day

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
J. D. Comer ◽  
S. Alvarez ◽  
S. J. Butler ◽  
J. A. Kaltschmidt
Keyword(s):  
Axon Guidance ◽  
Neuronal Development ◽  
Neurological Diseases ◽  
Commissural Axon ◽  
Commissural Axons ◽  
Guidance Cues ◽  
The Central Nervous System ◽  
Molecular Regulatory Mechanisms ◽  
Intermediate Targets ◽  
Developing Spinal Cord

Abstract During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.

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