Control of Neuronal Environment by Astrocytes - Essay Example

Control of Neuronal Environment by Astrocyes and their Role in Health and Disease of the Under the guidance of APA format Number of pages Control of Neuronal Environment by Astrocytes Until 25 years ago, the role of neurones was not much known and scientists thought that the purpose of the presence of these cells in abundance in the brain tissue was to provide only support. However, research on various mice models has led to the understanding of various homeostatic roles of these cells and their contribution to the health and disease of human beings. It has been reported that astrocytes play a major role in the synaptic transmission of messages, in the process of repair and regeneration, maintenance of extracellular ionic balance and transport and storage of some metabolites like glucose. In this article, the role of astrocytes in maintaining the neuronal environment in the brain has been explored with reference to health and disease in human beings. Structure of astrocytes Astrocytes are a type glial cells in the brain and the spinal cord which are star-shaped. They are also known as astrocytic glial cells. They serve many functions, the most important of which are nutrient supply to nervous tissue, biochemical support of endothelial cells which form the blood-brain barrier, maintenance of the balance of the extracellular ions and taking part in the process of repair and regeneration of the central nervous system following various injuries (Magistretti and Ransom, 2008). There re mainly 3 forms of astrocytes. They are fibrous astrocytes, protoplasmic astrocytes and radial astrocytes. Fibrous astrocytes are basically positioned in the white matter. They have few organelles. The cellular processes are 50-60 in number, long and unbranched (Magistretti and Ransom, 2008). When in close proximity, they physically connect the cells to the outerside of the capillary wall. The protoplasmic astrocytes are mainly found in the grey matter of the brain. In contrast to the fibrous cells, they have many organelles and have short, stubby and severely branched cellular processes. These processes are in contact with the blood vessels and also the pial surface. They also surround the neurons. The end-feet of these astrocytes cover the intraparenchymal surface completely and express glucose transporters Glu T type-1 (Magistretti and Ransom, 2008). Thus these cells predominantly function to take-up glucose. Fibrous astrocytes contain more intermediate filaments than protoplasmic astrocytes. The radial glia are mainly found in the vicinity of the ventricles. While some processes abut the piamater, other processes lie deep inside the gray mater. Some examples of radial astrocytes are Bergmann glia cells and Mueller cells of the retina. All the three types of cells send processes to form the pia-glial membrane when in close proximity to piamater. Astrocytes lack action potentials, synaptic potentials and axons. The ratio of astrocytes to neurons is usually 10:1 (Magistretti and Ransom, 2008). They occupy about 25- 50 percent of brain volume (Magistretti and Ransom, 2008). Astrocytes are present between the neuronal membranes and pericapillary spaces. By virtue of this position, these cells serve as intermediary elements between blood circulation which is the source of energy-rich substrates and neurones, which are the energy-consuming elements. The property of astrocytes which helps in performing such an intermediary function is the extensive connections each astrocyte establishes with other astrocytes by means of gap junctions which are nothing but specialized membrane structures. Gap junctions couple one astrocyte to another. These gap junctions are nothing but acqueous pores and they are permeable to various ions and molecules of less than 100 molecular weight. Some of the important biological molecules which have access through gap junctions are sugars, amino acids, nucleotides, small peptides, calcium ions, inositol phosphate and amino acids. The astrocytes release several endogenous compounds which control the permeability of the gap junction. Through this control, exchange of various metabolites like ions, small molecules, glucose and its derivatives and other elements is possible (Giume et al, 1997). Functions of astrocytes Ion homeostasis One of the most widely studied function of the astrocyte is the ion homeostasis. Astrocytes regulate the K+ ion concentration of the brain and contribute to homeostasis of brain tissue. Any neural activity leads to a rise in the K+ ions based on the intensity of action. Astrocytes remove the evoked increases of K+ ions and limits its accumulation to about 10-12 mM (Magistretti and Ransom, 2008). This is achieved basically through 2 mechanisms: increased uptake of K+ ions by astrocytes and redistribution of K+ ions through astrocytes known as K+ spatial buffering. The uptake of K+ by astrocytes is dependent on the glial Na+ pump that cotransports K+. Also, certain mechanisms called as Donnan forces propel KCl into glial cells when K+ concentrations increase in the brain tissue (Magistretti and Ransom, 2008). Synthesis of the neurotransmitters Astrocytes are intimately involved in the synthesis of glutamate which is the predominate excitatory neurotransmitter of the brain. The substance is present in millimolar concentrations in the brain and is packaged for synaptic release. Experiments with carbon-labeling have revealed the fact that astrocyte-derived glutamine is the main precursor of glutamate that is released synaptically (Magistretti and Ransom, 2008). The synthesis occurs through biochemical shuttle glutamate-glutamine cycle. Following release of glutamate from the presynaptic terminal, it is taken up by the astrocytes and in the astrocytes, glutamate is converted to glutamine with the help of glutamine synthetase which is dependent on the ATP. This enzyme is exclusively located in the astrocytes in the region of the processes surrounding the glutaminergic synapses. The released glutamine is taken up by the neurons with the help of specific uptake carriers (Magistretti and Ransom, 2008). Once inside the presynaptic vesicle, glutamine is again converted to glutamate with the help of glutaminase which is phosphte dependent and localized in the mitochondria near the synapses. The glutamate formed thus is packed into vesicles and kept ready for release. Thus through the glutamine-glutamate cycle, resynthesis of glutamate occurs and toxic accumulation of glutamine is prevented. This cycle is very rapid (Magistretti and Ransom, 2008). Removal of neuro-transmitters Though glutamate is an important neurotransmitter in the brain, it is also a potent neurotoxin and has been implicated in various pathological conditions of the brain like epilepsy, amyotrophic lateral sclerosis, stroke and epilepsy. Astrocytes have glutamate transporters which are highly efficient in removing synaptically released glutamate. The glutamate receptors uptake is driven by electrochemical gradients like Na+ and K+. In the absence of astrocytes, neurons are 100 times more susceptible to the toxicity of glutamate and its products (Magistretti and Ransom, 2008). Astrocytes which face the synaptic cleft have higher concentrations of powerful glutamate transporters like GLAST and they take up most of the glutamate release into the synaptic clefts. There are ofcourse some regions in the brain wherein about 20 percent of the glutamate is transmitted across the synaptic cleft into the postsynaptic neuron (Magistretti and Ransom, 2008). Metabolic coupling with neurones The end-feet of the astrocytes surround all the capillaries of the brain and other processes of the astrocytes surround the synaptic contact areas. Also, astrocytes house reuptake sites for various neurotransmitters like glutamate in addition to a variety of receptors. The astrocytic end feet are rich in specific glucose transporter GLUT 1. Glutamate is an excitatory neurotransmitter and release of this hormone causes stimulation of glycolysis during which glucose is taken in lactate is produced. Recent research has shown that release of glutamate is dependent on calcium ion concentration (Santello and Volterra, 2008). The metabolic effect of glutamate is effected by the glutamate transporters which are selectively expressed in the astrocytes, especially the GLAST type. Thus synaptic activity triggers the astrocytes to uptake glucose from the circulation. This function is ofcourse executed by the astrocytes near the circulation and synaptic clefts (Magistretti and Ransom, 2008). The amount of glucose uptake depends on the extent of neuronal activity. Thus glucose uptake is coupled with neuronal activity. The critical enzyme for this coupling is Na-K-ATPase which is stimulated by the glutamate. The stimulation occurs by increasing the intracellular concentrations of Na+ through Na+ dependent glutamate uptake by various glutamate transporters. The glycolytic process which is stimulated by the glutamate results in 2 lactate molecules per glucose molecule. It is yet unclear whether lactate from this source is transferred to neurones for the purpose of energy. Though in vitro studies have reported maintenance of synaptic or axonal activity with just lactate alone, such an effect in vivo has not yet been ascertained. The property of Glutamate-mediated neuron–glia metabolic interactions has been employed as the basis for various functional brain imaging techniques like positron emission tomography (Magistretti and Ransom, 2008). Energy storage Glycogen is the largest energy reserve in the brain and spinal cord and is almost exclusively localized in the astrocytes. The levels of glycogen in these cells are much lower than the concentration levels on the liver and muscle cells. However, the concentrations are dependent on the synaptic activity intensity and various neurotransmitters (Magistretti and Ransom, 2008). While somarosensory stimulation results in the mobilization of glycogen in the corresponding area of somatosensory cortex and concerned subcortical relays, administration of anesthesia in which there is minimal synaptic activity causes rise in glycogen levels dramatically. Acute or chronic neuronal loss as in Alzheimers disease causes plastic adaptations of the regulation of glycogen resulting in glycogen deposition. Even in acute lesions, glycogen deposits can be there. Whenever there is acute shortage of glucose supply, glycogen is degraded to provide fuel to brain (Magistretti and Ransom, 2008). Modulation of synaptic transmission Research has shown that astrocytes in the supraoptic nucleus of the hypothalamus rapidly change their morphology and affect heterosynaptic transmission between various neural cells. In the hippocampus, the astrocytes release ATP (Piet, Vargová, and Syková, 2004). This molecule is hydrolyzed by ectonucliotidases to adenosine which suppress synaptic transmission by acting on the adenosine receptors of the neurones. Glial signaling Activity of neurons causes Ca2+ waves in adjacent astrocytes. These rates occur at the rate of 10-20 micrometer per sec. The waves are involved in the formation and transmission of inositol-1,4,5-trisphosphate and subsequent release of ATP (Magistretti and Ransom, 2008). This phenomenon has been mainly studied in retina. The role of calcium waves is not fully understood. However, it has been thought that these waves coordinate the activity of astrocytes and influence the neurons in the vicinity. There are reports that calcium waves induce action potentials in the neurons of the hippocampus and also in the retina (Magistretti and Ransom, 2008). Blood brain barrier The end-feets of the astrocytes encircle the endothelial cells and form part of the blood brain barrier. However, most researchers argue that this part of barrier is the effective one and rather, the basal lamina and tight junctions have a more effective role on the functioning of the blood brain barrier (Pascual, Casper, Kubera et al, 2005). Vasomodulation According to Parri and Crunnelli (2003), astrocytes act as intermediaries for regulation of the blood flow by the neurones. Myelination Induction of the electrical activity in the neurons causes release of ATP which acts on the astrocytes and stimulates the release of cytokine leukemia inhibitory factor, This helps in the formation of myelin by the oigodendrocytes (Ishibashi Dakin and Stevens, 2006). Role on repair following brain injury Whenever the central nervous system or CNS is inflicted with injury, the appearance of the astrocytes changes and the cells undergo hypertrophy. This is known as astrogliosis or reactive gliosis (Nisson and Penky, 2007). The characteristic feature of the hypertrophy is enlargement of the cellular processes of the cells. During the process of hypertrophy, several proteins are upregulated. These proteins are intermediate filaments, vimentin, proteins glial fibrillary acidic protein or GFAP, nestin and synemin. Intermediate filaments, also known as nanofilaments, serve to form the cytoskeleton of the cells along with actin filaments and microtubules. There are about 65 intermediate filament protein identified so far. The proteins are expressed in a complex manner based on the developmental stages of the brain. They are dynamic and a dynamic equilibrium exists between these filaments and a pool of soluble subunits (Nisson and Penky, 2007). In the absence of brain or spinal pathology, the astrocytes are non-reactive. The main intermediate filaments in non-reactive astrocytes are glial fibrillary acidic protein and vimentin, whereas in reactive astrocytes, both these filaments are absent and nestin and synemin are predominant intermediate filaments. The major intermediate filament proteins in mature astrocytes are glial fibrillary acidic protein and vimentin. Also, in mature astrocytes, the processes are fine and extend from the main cellular processes giving a typical bushy appearance to each and every cell. However, the intermediate filament network is restricted only to the main processes and the soma of the astrocyte cells. Some reactive astrocytes like in denervated hippocampus and cortical pathological regions have thickened main cellular processes (Nisson and Penky, 2007). Astroglial cells with GFAP intermediate filaments have a major role in the baseline neurogenesis of adult mammalian central nervous system. Research has shown that astrocytes control neurogenesis in the dentate gyrus of the hippocampus and subventricular zones (Nisson and Penky, 2007). These 2 zones have high new neurone turn out. Hence researchers are of the opinion that astroglial cells may have control on the neurogenesis of the adults and may act as precursors of neurones in the adulthood (Nisson and Penky, 2007). The importance of GFAP has been possible to understand by studying mice with knocked out GFAP. It has been found that astrocytes lacking GFAP have disturbed neuroplasticity and can contribute to long-term depression, increased risk of ischemia and late onset dysmyelination. However, it has not been possible to ascertain the mechanisms of these manifestations (Nisson and Penky, 2007). An understanding of the role of intermediate filament upregulation in reactive astrocytes has been possible through research on various mice models in which the mice were inflicted with central nervous system trauma. Through such a research, it has come to the understanding of experts that reactive astrocytes have a major role in post-traumatic healing (Nisson and Penky, 2007). There are reports that astrocytes get involved in synaptic regeneration following trauma of the central and spinal nervous system. Lesions of entorhinal cortex and hippocampus trigger extensive reactive gliosis (Nisson and Penky, 2007). Due to their abundance and morphological characteristics, astrocytes are in direct physical contact with any cell that shifts places or moves from one place to another (Nisson and Penky, 2007). Reactive astrocytes have a beneficial role in acute stage because it facilitates repair. However, in later stages, it inhibits CNS regeneration. The fact that astrocytes inhibit CNS regeneration in later stages comes from various studies on transgenic mice which express inhibitor NF kappa B in astrocytes or are deficient in EphA4 (Nisson and Penky, 2007). Astrocytes are very important for the homeostatic regulation of plasticity. The cells balance the level of activity between neurones by regulating the number of synaptic connections (Giume et al, 1997) In times of injury, depletion of the intermediate filament proteins occurs which makes astroglial cells more immature and this supports regeneration of the central nervous system. The state of cellular differentiation and functions of the cells is altered by the composition and abundance of various intermediate filaments (Nisson and Penky, 2007). Role in glucose metabolism The main metabolic substrate for the brain is glucose (Giume et al, 1997). Glucose is transported into the astrocytes by non-insulin sensitive glucose transporter GLUT-1 which has high affinity for glucose (Giume et al, 1997). After entry of glucose into the astrocyte cell, glycolysis through pentose phosphate shunt occurs. Glucose which does not undergo glycolysis gets converted in to glycogen which is stored in the astrocytes. Astrocytes are the only brain cells which have the capacity to store glycogen. Glucose utilization in brain is controlled by hexokinase catalyzed key step reaction. Most astrocytes lack the enzyme glucose-6-phosphatase and hence the end product of glycogenolysis in brain is glucose-6-phosphate and not glucose (Giume et al, 1997). Plasma membrane of the astrocytes is not permeable to this product and hence gets accumulated in the cell. This product gets glycolysed to lactate which is permeable to plasma membrane and thus the neurons can make use of it (Giume et al, 1997). Lactate transport through astrocytes is mediated by a specific carrier and lactate is used in high quantities in the cells. Lactate is not only a source of energy, but also an important substrate for brain cells, especially during brain development. The lactate is not only used by astrocytes but also transported to the extracellular medium in the form of tricarboxylic acid metabolites like citrate. Such a phenomenon is not observed in neurons due to lack of pyruvate carboxylase enzyme (Giume et al, 1997). Synaptic activity Research has shown that astrocytes are integral parts of synaptic connections and they have the ability to sense and modulate synaptic activity. Through synaptic signals, they directly change the number of synaptic connections. They indirectly affect synaptic activity by modifying the morphology of axons and dendrites (Slezak, Pfrieger, Soltys, 2006). Purines directed brain repair Astrocytes are the main source of purines in the brain which play an important role in the pathophysiology of many acute and chronic brain disorders. The purines are either adenine-based or guanine-based. the cells express several receptors for the adenine-based purines. Once released from the astrocytes, the purines are subjected to various enzymes like adenosine deaminase and nucleotidase. Adenosine stimulates astrocyte proliferation through A2 receptors and inhibits astrocyte proliferation through A1 and A3 receptors. It has been proposed that adenosine and guanine based purines which are released from pathological conditions of the brain trigger the proliferation of astrocytes and initiate brain repair mechanisms (Ciccarelli et al, 2001). Role during neurogenesis During neurogenesis, the astrocytes play an important role in helping the neurons migrate to correct destination, promote outgrowth of neurites and direct growing neurites to their place of destination. Such a homeostatic control by astroctyes is possible by virtue of their presence near the blood brain barrier and neuronal synapses (Ciccarelli et al, 2001). Conclusion Astrocytes have multiple physiological brain functions. They not only participate in the neuronal development and synaptic activity, they also play a role in the homeostatic control of the extracellular environment of the brain tissue. They also take part in various processes subsequent to brain injury contributing to the repair of brain damages and limiting the process of repair and regeneration. Thus astrocytes function to maintain the neuronal environment in the brain. References Ciccarelli, R., Ballerini, P., Sabatino, G., et al (2001). Involvement of astrocytes in purine-mediated reparative processes in the brain. Int. J. Devl Neuroscience 19, 395–414 Giaume, C., Tabernero, A., and Medina, J.M. (1997). Metabolic Trafficking Through Astrocytic Gap Junctions. Glia, 21, 114- 123. Ishibashi, T., Dakin, K., Stevens, B., Lee, P., Kozlov, S., Stewart, C., Fields, R. (2006). Astrocytes promote myelination in response to electrical impulses. Neuron, 49 (6), 823–32 Magistretti, P.J., and Ransom, B.R. (2008). Astrocytes. Neuropsychopharmacology: The Fifth Generation of Progress, 133-145. Nisson, M., and Pekny, M. (2007). Enriched Environment and Astrocytes in Central Nervous System. J Rehabil Med., 39, 345- 352. 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