Opera Medica et Physiologica

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Printed July 23, 2016;
Published ahead of print July 06, 2016; Printed July 23, 2016; OM&P 2016 Volume 2 Issue 2, pages 122-140; doi:10.20388/OMP2016.002.0029
Abstract Full Text

Astrocytes perform fundamental housekeeping functions in the central nervous system and through bidirectional communication with neurons are thought to coordinate synaptic transmission and plasticity. They are also renowned actors in brain pathology. Reactive gliosis and neuroinflammation are featured by many (if not all) acute and chronic neurodegenerative pathologies including Alzheimer’s disease (AD). The Ca2+/calmodulin-activated phosphatase calcineurin (CaN) plays a central role in the pathology-related changes of astroglial cells mainly through activation of the inflammation-related transcription factors Nuclear Factor of Activated T-cells (NFAT) and Nuclear Factor kB (NF-kB). In this contribution we focus on the mechanistic aspects of CaN signalling in astrocytes. We analyze the astroglial Ca2+ signalling toolkit in the context of Ca2+ signals necessary for CaN activation and focus on the astroglial CaN signalling through its direct target, NFAT, as well as the intricate relationships between CaN and NF-kB activation pathways.The majority of data about CaN-mediated signalling in astrocytes point to the role for CaN in pathology-related conditions while very little is currently known about signalling and function of astroglial CaN in physiology.

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OMP_2016_02_0029.pdf1.07 MB

Printed July 23, 2016;
Published ahead of print July 05, 2016; Printed July 23, 2016; OM&P 2016 Volume 2 Issue 2, pages 141-152; doi:10.20388/OMP2016.002.0028
Abstract Full Text

Maintenance of genome stability in the face of DNA damage is essential for cellular homeostasis and prevention of cancer and brain degeneration. The DNA damage response (DDR) is a complex response that is rapidly activated when a DNA lesion occurs in chromosomal DNA. Mutations affecting the proteins involved in the DDR can lead to genomic instability syndromes that involve tissue degeneration, cancer predisposition, premature aging, and brain mal-development and degeneration. Mutation of the kinase ATM leads to a prototype genomic instability syndrome, ataxia-telangiectasia (A-T). A-T is characterized by progressive cerebellar degeneration, immunodeficiency, genome instability, premature aging, gonadal dysgenesis, extreme radiosensitivity, and high incidence of lymphoreticular malignancies. One of the most devastating symptoms of A-T — cerebellar ataxia — develops progressively into general motor dysfunction. Based on our previous studies we hypothesized that the neurological deficits in genomic instability disorders stem (at least in part) from significant reduction in functionality of glial cells. We further hypothesized that impaired vascularization affects the environment in which the neurons and glial cells function, thereby reducing neuronal cell functionality. We found that ATM deficiency led to aberrant astrocytic morphology and alterations of vasculature both in cerebellum and the visual system. Moreover, we found reduced myelin basic protein immunoreactivity and signs of inflammation in ATM-deficient cerebella and optic nerve.  Interestingly, similar findings have been reported in patients with other genomic instability disorders. These observations bolster the notion that astrocyte-specific pathologies and hampered vascularization and astrocyte-neuron interactions in the CNS play crucial roles in the etiology of genome instability brain disorders and underlie brain degeneration at specific sites.

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OMP_2016_04_0028.pdf950.57 KB

Printed July 23, 2016;
Published ahead of print July 04, 2016; Printed July 23, 2016; OM&P 2016 Volume 2 Issue 2, pages 153-163; doi:10.20388/OMP2016.002.0030
Abstract Full Text

The name astroglia unifies many non-excitable neural cells that act as primary homeostatic cells in the nervous system. Neuronal activity triggers multiple homeostatic responses of astroglia that include increase in metabolic activity and synthesis of neuronal preferred energy substrate lactate, clearance of neurotransmitters and buffering of extracellular K+ ions to name but a few. Many (if not all) of astroglial homeostatic responses are controlled by dynamic changes in the cytoplasmic concentration of two cations, Ca2+ and Na+. Intracellular concentration of these ions is tightly controlled by several transporters and can be rapidly affected by activation of respective fluxes through ionic channels or ion exchangers. Here we provide a comprehensive review of astroglial Ca2+ and Na+ signalling.

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OMP_2016_02_0030.pdf457.26 KB

Printed July 23, 2016;
Published ahead of print July 03, 2016; Printed July 23, 2016; OM&P 2016 Volume 2 Issue 2, pages 164-171; doi:10.20388/OMP2016.002.0031
Abstract Full Text

Thyroid hormones (THs) are essential for the development and function of the central nervous system (CNS), not only for neuronal cells but also for glial development and differentiation. In adult CNS, both hypo- and hyper-thyroidism may affect psychological condition and potentially increase the risk of cognitive impairment and neurodegeneration including Alzheimer’s disease (AD). We have reported non-genomic effects of tri-iodothyronine (T3) on microglial functions and its signaling in vitro (MORI et al., 2015). Here we report the effects of hyperthyroidism on glial cells in vivo using young and old male and female mice. Immunohistochemical analyses showed glial activation are sex- and age-dependent. We also injected fluorescent-labeled amyloid β peptide (Aβ1-42) intracranially to L-thyroxine (T4)–injected hyperthyroid model mice and observed sex-dependent microglial phagocytosis in vivo as well. These results may partly explain the gender- and age-dependent differences in neurological and psychological symptoms of thyroid dysfunction.

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OMP_2016_02_0031.pdf1.23 MB

Printed June 30, 2016;
Published ahead of print June 21, 2016; Printed June 30, 2016; OM&P 2016 Volume 2 Supplement S 2
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autors index.pdf116.71 KB

Printed March 04, 2016;
Published ahead of print January 18, 2016; Printed March 04, 2016; OM&P 2016 Volume 2 Issue 1, pages 1-10; doi:10.20388/OMP2016.001.0019
Abstract Full Text

The common denominator of neurodegenerative diseases, which mainly affect humans, is the progressive death of neural cells resulting in neurological and cognitive deficits. Astroglial cells are central elements of the homoeostasis, defence and regeneration of the central nervous system, and their malfunction or reactivity contribute to the pathophysiology of neurodegenerative diseases. Pathological remodelling of astroglia in neurodegenerative context is multifaceted. Both astroglial atrophy with a loss of function and astroglial reactivity have been identified in virtually all forms of neurodegenerative disorders. Astroglia may represent a novel target for therapeutic strategies aimed at preventing and possibly curing neurodegenerative diseases.

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OMP_2016_01_0019.pdf584.08 KB

Printed March 04, 2016;
Published ahead of print January 17, 2016; Printed March 04, 2016; OM&P 2016 Volume 2 Issue 1, pages 11-26; doi:10.20388/OMP2016.001.0024
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A conspicuous ability of the mammalian brain to integrate and process huge amount of spatial, visual and temporal stimuli is a result of its enormous structural complexity functioning in an integrated way as a whole. Here we review recent achievements in the understanding of brain structure and function. A traditional view on the brain as a network of neurons has been extended to the more complicated structure including overlapping and interacting networks of neurons and glial cells. We discuss artificial versus natural neural networks and consider a concept of attractor networks. Moreover, we speculate that each neuron can have an intracellular network on a genetic level, based and functioning on the principle of artificial intelligence. Hence, we speculate that mammalian brain is, in fact, a network of networks. We review different aspects of this structure and propose that the study of brain can be successful only if we utilize the concepts recently developed in nonlinear dynamics: the concept of integrated information, emergence of collective dynamics and taking account of unexpected behavior and regimes due to nonlinearity. Additionally, we discuss perspectives of medical applications to be developed following this research direction.

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OMP_2016_01_0024.pdf1.8 MB

Printed March 04, 2016;
Published ahead of print January 17, 2016; Printed March 04, 2016; OM&P 2016 Volume 2 Issue 1, pages 27-33; doi:10.20388/OMP2016.001.0022
Abstract Full Text

Classically, the central nervous system (CNS) was considered to contain neurons and three main types of glial cells - astrocytes, oligodendrocytes, and microglia.  Now, it has been clearly established that NG2-glia are a fourth glial cell type that are defined by their expression of the NG2 chondroitin sulfate proteoglycan (Cspg4).  NG2-glia are also known as oligodendrocyte precursor cells (OPCs) and express the alpha receptor for platelet-derived growth factor (Pdgfra) as well as other oligodendrocyte lineage markers. NG2-glia are most numerous during CNS development when they are responsible for massive generation of oligodendrocytes, the myelin-forming cells of the CNS. A significant population of NG2-glia persist in the adult CNS, where they generate oligodendrocytes throughout life. A unique feature of NG2-glia is that they receive synaptic inputs from neurons and are able to respond rapidly to neurotransmission via their specific ion channel and receptor profiles. Moreover, synaptic and neuronal integrity depend on NG2-glia. Notably, concomitant disruption of NG2-glia, myelin and neurotransmission are key features of many neuropathologies, including Multiple Sclerosis and Alzheimer’s disease (AD). The fact that neurotransmission both regulates and is reliant on NG2-glia and myelin raises the ‘chicken and egg’ question of what comes first – disruption of NG2-glia/myelin or synapses/neurons. It is more useful to think of neurons, NG2-glia and oligodendrocytes/myelin as being functionally integrated and interdependent units, whereby disruption of any one can result in a vicious cycle with potentially devastating effects on CNS function.

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OMP_2016_01_0022.pdf909.28 KB

Printed March 04, 2016;
Published ahead of print January 17, 2016; Printed March 04, 2016; OM&P 2016 Volume 2 Issue 1, pages 34-43; doi:10.20388/OMP2016.001.0017
Abstract Full Text

Astrocytes are now recognised as important contributors to synaptic transmission control. Dopamine is a key neuromodulator in the mammalian brain and establishing the potential extent of its actions involving astrocytes is vital to our overall understanding of brain function. Astrocyte membranes can express receptors for dopamine, as well as dopamine transporters, but the full effects of dopamine on astrocytic physiology are still uncertain and its mode of action controversial. Here we overview the developing field of astrocyte-dopamine interaction, focusing on how dopamine affects the pre-eminent astrocytic intracellular signalling messenger – Ca2+ – and the available evidence for astrocyte-mediated effects of dopamine on neurons. We then discuss some of the methodological issues that need to be addressed to help move the field forward.

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OMP_2016_01_0017.pdf817.55 KB

Printed March 04, 2016;
Published ahead of print January 17, 2016; Printed March 04, 2016; OM&P 2016 Volume 2 Issue 1, pages 44-54; doi:20388/OMP2016.001.0020
Abstract Full Text

Most of the human brain mass is occupied by the neocortex, which consists of neurons and non-neurons. The latter cells include astrocytes, a heterogeneous glial cell type. While astrocytes have been considered as neuronsubservient entities for almost a century, it is now becoming evident that they are essential in providing homeostatic support to neural networks and that they also actively participate in information processing in the brain. Astrocytes get excited when neurotransmitters bind to their membrane receptors and feed-back by releasing their own signals. This involves vesicles, which store chemicals termed gliotransmitters or more generally gliosignaling molecules. In the former case chemical messengers get released from astrocytic sites proximal to the synapse, which defines communication to occur in the micro-space of contact between the synapse and the astrocyte. In contrast gliosignaling molecules may also be released into the extracellular space. This mode of release resembles the endocrine system. Hence astrocytes are considered to be part of the gliocrine system in the brain, where the glymphatic system mediates the convection of released molecules. This complex system not only plays a role in cell-to-cell communication but also synchronizes the provision of energy for neural networks. Astrocytes contain glycogen, a form of energy store. Excitation of astrocytes by volume transmitters, such as noradrenaline , released by locus coeruleus neurons, activates adrenergic receptors and stimulates glycogenolysis, providing lactate. This chapter briefly reviews how noradrenaline and astrocytes operate to synchronize excitation and energy provision. Moreover, Ca2+ -dependent fusion of the vesicle membrane with the plasma membrane in astrocytes is discussed.

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OMP_2016_01_0020.pdf1.74 MB

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