Preface

It was the German pathologist Rudolf Virchow who described glial cells for the first time. In 1846, he analyzed postmortem human tissues, and considered those cells to be merely a "glue" having only a passive supporting role. Nowadays, glial cells are considered more than passive components and have become active partners with neurons. Thus, they seem to be much more actively involved in brain function than was formerly thought. Glial cells comprise microglia, oligodendrocytes, and astrocytes in the central nervous system, and Schwann cells, satellite cells, and enteric glial cells in the peripheral nervous system. It is already well established that neuron– glia interactions control several processes of brain development such as neurogenesis, myelination, synapse formation, neuronal migration, proliferation, differentiation, and even neuronal signaling. In all these processes astrocytes have important roles: neurotransmitter clearance, ion buffering, and neuronal trophic support by secreting members of the epidermal growth factor family, transforming growth factor, neuregulin, fibroblast growth factor, nerve growth factor, and ciliary neurotrophic factor, for instance. Moreover, astrocytes are also involved in other functions, such as synapse development, blood–brain barrier formation, and neurogenesis.

Despite all the roles of glial cells in a healthy nervous system, they are also involved in neurological disorders or diseases. In response to injury and diseases, glial cells suffer a process termed astrogliosis that induces proliferation, progressive cell hypertrophy, progressive alteration in molecular expression, and scar formation. Studies have demonstrated that the malfunction of glial cells plays a pivotal role in several neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease (AD), and multiple sclerosis (MS). During the development of several neurological diseases, there is an increase in the inflammation process that is related to the progression and worsening of the symptoms.

In this book, we will highlight the role played by glial cells in the central and peripheral nervous systems in healthy and unhealthy individuals by giving particular attention to the enteric nervous system (ENS). Among all processes involved, we will specifically discuss the importance of ENS in the control of gut homeostasis, in the interaction with the immune system, and its participation in pathological conditions such as metabolic syndrome.

In particular, the relevance of astrocytes will be explored during synaptic transmission and regulation of plasticity by releasing gliotransmitters. Ultimately, we will highlight the influence of astrocytes during the development of a number of neurodegenerative diseases, such as MS and AD. We will focus on how the serum levels of the astrocytic protein S100B can be used as a biomarker for clinical decisions for the onset and progression of neurodegenerative diseases.

**II**

**Chapter 7 131**

Astrocytes in Pathogenesis of Multiple Sclerosis and Potential

*by Izrael Michal, Slutsky Shalom Guy and Revel Michel*

Translation into Clinic

**1**

Section 1

Neuroscience

Section 1 Neuroscience

**3**

**Chapter 1**

**Abstract**

Hemichannels

stimulated conditions is discussed.

**1. Introduction**

**Keywords:** connexin 43, astrocyte, gliotransmission, brain, neuron

*Juan A. Orellana*

Synaptic Functions of Astroglial

In recent decades, astrocytes have gained ground in their protagonist role at the synapses, challenging the old-historic idea that neurons are the unique functional units in the nervous system. Although for a long time considered merely supportive elements, astrocytes are now recognized as a source of gliotransmitter release that regulates synaptic transmission and plasticity. Despite the initial evidence that supported gliotransmission depends on intracellular Ca2+-mediated vesicular release, recent data indicate that hemichannels may constitute an alternative non-vesicular route for gliotransmitter efflux. These channels are plasma membrane channels formed by the oligomerization of six connexins around a central pore. Hemichannels are permeable to ions and signaling molecules—such as ATP, glutamate, and Ca2+—constituting a pathway of diffusional interchange between the cytoplasm and the extracellular milieu. Connexin 43 is the main hemichannelforming protein in astrocytes and is highly regulated under physiological and pathological conditions. In this chapter, the available data supporting the idea that hemichannels are chief components in tuning the synaptic gain in either resting or

In order to ensure a proper response to external stimuli, organisms have created complex and coordinated neural structures that allow the sophisticated analysis of information. As the central nervous system (CNS) evolved from a basic network structure to compacted ganglia and centralized brains, two types of connections emerged as specialized structures favoring the integration of neural networks [1]. In 1897, Sherrington proposed the point of functional contact between neurons as the specific area at which transfer of information takes place and named it "synapsis," soon shortened to the "synapse," from the Greek word *sunáptō* (to clasp) [2]. This specialized structure is known today as the chemical synapse and transfers electrical information unidirectionally from presynaptic to postsynaptic neurons through the release of neurotransmitters, which, acting upon postsynaptic receptors, initiate a second electrical signal [1]. In the late 1950s, Furshpan and Potter reported a series of experiments revealing that synaptic transmission in the crayfish is bidirectional and voltage-dependent, two properties substantially out of range of the criteria established for chemical transmission [3]. This study revealed the pioneer evidence in favor of the existence of electrical synaptic transmission. Unlike chemical synapse, the electrical synapse permits the bidirectional

### **Chapter 1**
