ROLE OF ASTROCYTES IN CENTRAL NERVOUS SYSTEM, DISEASE IMPLICATIONS AND NEW PHYSIOLOGICAL IMPLICATIONS IN MEMORY AND LEARNING

Inside Central Nervous System (CNS) appears neurons and glia cells. There are more glial cells than neurons and have more functions than neurons. Glia name represents different kind of cells, ones from neural origin (astrocytes, radial glia, and oligodendroglia), and others from blood monocytes (microglia). During ontogeny, neurons appear first (rat fetal 15th) and after astrocytes (rat fetal 21th) indicating a bigger importance function in the CNS. Also, during the phylogeny, reptiles have less astrocytes compared to neurons and in humans, astrocytes are double in number than neurons. This data, perhaps means that astrocytes are more special cells and work in memory and learning? Astrocytes have an important role in different mechanisms protecting CNS across the production of antioxidant and anti-inflammatory proteins, cleaning extracellular medium and helping neurons to communicate with each other correctly. Inflammatory mediators production are important to prevent changes in normal physiology. But, excessive or continue production leads to many diseases, such as Alzheimer's disease (AD), Sclerosis Lateral Amyotrophic (ELA), Multiple sclerosis (MS), and neurodevelopment diseases, like Bipolar disorder, Schizophrenia, and Autism's symptomatology. Different drugs and thecniques can reverse oxidative stress and/or inflammatory excess. This review is intended to serve as an approximation to the field.


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between astrocytes exists and when it is necessary, they start a big communication between them and with neurons, oligodendroglia, and microglia.
Future hypothesis looking for the role of astrocytes in mammalian functions will be necessary and a new field in the astrocytes job in the nervous system has been opened now. That will provide a new direction for future interventions in CNS diseases.
Astrocytes respond to changes in their microenvironment because they have two types of processes. Perisynaptic processes, with fine extensions to the interneuronal synapse and vascular processes with final lengthenings (endfeet) communicating with blood vessels. Perisynaptic processes express receptors for neurotransmitters, cytokines, chemokines, growth factors, and ion channels.
Furthermore, transporters and receptors for glutamate, so controlling neuronal glutamatergic neurotransmission [5,6]. The endfeet in astrocytes express glucose transporters and aquaporins 4 and covers most of the blood vessels [6].
Moreover, astrocytes are territorial cells with processes controlling territory with only a few overlap between neighboring astrocytes [7] which are interconnected into functional networks [8,9]. It has been demonstrated that astrocyte cell contact with up to 2,000,000 synapses [4,10] and this interaction depends on changes in neuronal activity. Thanks to that astrocytes offer energy to neurons by lactate shuttle [11,12] and modulate Ca2+ variations [13]. Respecto to gender differences, data from rodents demonstrated significant differences in glia between males and females [14,15]. Testosterone is produced by the testis of male change to estradiol in the brain. In the male preoptic area, astrocytes are more ramified with more density of dendritic spines. Also, have a higher density of microglia with reduced branching pattern. In neurodevelopment, disorders like 6 autism, different forms of schizophrenia, and early-onset bipolar disorder, males are at higher risk than females to develop these disorders and have been published the role of glia in all of them. Autism is four to eight times more common in males [16,17] with hypermasculinized phenotypes [18] (Fig. 2). there are two types of astrocytes, hypertrophic, and those that form scars [19].
The changes affect different pathologies such as Alzheimer's disease, Huntington's disease, ischemic stroke, and epilepsy. In Alzheimer's disease (AD) and multiple sclerosis (MC) reduction in brain weitht is detected, with increase in grooves and a loose of water in general. During the day, astrocytic cells are swollen with fluid that they pour out at night cleaning the brain from toxins, 7 proteins, and unwanted molecules. When astrocytes are damaged (Fig. 3), during the waking period, cannot return water inside, losing the possibility to clean toxins at the following night and increasing the presence of toxins. Astrocytes give glutamine to neurons and eliminate glutathione from the synapsis. In AD, neurons die because hyper-phosphorylation of TAU (π protein) occurs. Probably astrocytes are involved in this process because reduction of glutamine to neurons or/and elimination of glutathione will not occur. Furthermore could be a reduction in ATP, produced by mitochondria damaged [3]. Inside the brain, oxygen is necessary and cross from circulatory system to extracellular space between brain cells. If circulation, with the good function of the heart, does not produce, oxygen will be going down and brain cells could have problems to produce adenosine triphosphate (ATP) and transport messenger from neuron 8 body to synapse. So, cardiology specialists, neurologists, psychologists, and medical specialists in the developing brain will be in contact from now to the future [19]. On the other hand, astrocytes are involved in non-physiological pain [20].
Communication between the cells of the sensory ganglia could be important in the treatment of chronic pain [21,22] (Fig.4).

Figure 4: Communication between astrocytes, neurons and microglia in pain situations.
Activation of nociceptors causes the induction of cytokines, chemokines, BDNF and neurotrophic factors producing changes an increase of persistent pain.

Astrocytes and inflammation
Analogously to microglia, the role of astrocytes in inflammation has been studied.
During cerebral ischemia, these cells act as protectors. On the contrary, against lipopolysaccharide-mediated inflammation (LPS), they appear to be detrimental.
However, in the cells of the retina, it has been demonstrated an anti-inflammatory and neuroprotective effect through the production of lipoxins, against acute and chronic lesions [23]. Furthermore, the cytokine IL-33 produced by astrocytes has an essential role in the development of neuronal circuits [24]. Other studies showed that the activation of certain transcription factors are involved in producing protective (STAT3) [25] or injurious effects (NF-ᴋB) [26]. Moreover, there is also a correlation between IL-1α and the greater number of GFAPimmunoreactive astrocytes [27]. On the other hand, in multiple sclerosis, TNF-α alters synaptic transmission affecting the cognitive level [28].
Inflammatory signals are present in the mild cognition impairment (MCI) patient before they develop AD [29]. Inflammation is a crucial factor in AD progression as is seen in activating microglia and increasing reactive astrocytes in these patients. Astrocytes can change their shape during hypertrophy and increase their ramifications, moving to the injury site [30]. Patients with AD present reactive astrocytes as detected by PET (Positron Emission Tomography) imaging [31,32] and also, before the formation of plaques in APP transgenic mice [33]. In reactive astrocytes, the level of gliotransmitters (including glutamate, ATP, dserine and GABA) can produce inhibition of neuronal activity [34]. In amyloid plaques, an increase in GABA protein has been detected in reactive astrocytes which surround the plaques and that trigger more release into the extracellular space [34,35]. There is a consensus that the role of GABA, is protecting neural cells in the brain [35]. Furthermore, Delekate's group showed that astrocytes in APP/PS1 mice (Mice carrying the human Swedish amyloid precursor protein and the Δe9 presenilin 1 mutation) increase the release of ATP surrounding the plaques. This happens because the Ca2+ concentration rises inside the cell [36].
The latter gives us the idea that an increase in ATP in astrocytes and neurons    Due to the high metabolic rate of the neurons, these cells produce more free radicals than other cells of the nervous system. Neurons also have a reduced ability to eliminate reactive oxygen species, which makes them highly vulnerable to oxidative stress [57]. In many neurodegenerative disorders have been detected an increase of free radicals that can induce aggregations of proteins and it happens in many diseases, such as PD, AD, ALS, HD, etc. [58][59][60][61]. In sporadic cases of Alzheimer's disease, age factors are important and can influence the Aβ-amyloid processing by losing mitochondrial function and excessive ROS production [62]. Alternatively, α-synuclein aggregates caused by dopaminergic neurons in Parkinson's disease disrupts mitochondrial function and then producing oxidative stress [63,64]. Moreover, α-synuclein aggregation can be produced by an increase in oxidative stress [65]. One form of amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) mutation [66], presents the affectation of the antioxidant molecules balance with the increase in oxidative stress [67], due to aggregation of SOD 1 [68]. The diseases indicated above and together with HD share aggregation process and oxidative stress that together produce a vicious cycle [69].

Neurodegeneration Mechanisms
In the neurodegenerative cascade, several basic mechanisms can intervene, such as apoptosis, necrosis, autophagy, retrograde neurodegeneration, Wallerian degeneration, demyelination and astrogliopathy [70]. There is evidence of apoptotic mechanisms in animal models of various neurodegenerative diseases, but the evidence in human tissues is limited. The activation of caspase-1, -3, -8 and -9 and the release of cytochrome c observed in models of Apathy has multifactorial symptoms, as behavioural, cognitive, and emotional facets including impaired motivation and reduced goal-directed behaviour.
Apathy belongs to schizophrenia, bipolar disorders and autism's negative symptomatology. The molecular mechanisms are still poorly studied [78,79].
Correlations between apathy with specific brain regions and executive functions have been shown (the anterior cingulate cortex, orbitofrontal cortex and the ventral and dorsal striatum). It is considered the major neuropsychiatric symptom in both acquired and neurodegenerative disorders such as strokes [80], AD [81], ELA [82] or Parkinson's disease [83]. All these disorders have a disturbance of the normal balance of neurotransmitters and are associated with anomalies in specific brain regions and inflammatory pathways leading to glia activation and finally neuronal and neural loss [84]. In MS there is a decomposition of the bloodbrain barrier (BBB), death without regeneration of oligodendrocytes, loss of myelin, axonal degeneration and reactive gliosis of astrocytes and activation of microglia [85,86]. In the disease, inflammation plays an important role with an increase in cytokines and chemokines. In the pathophysiology of MS, the BBB is compromised, causing activation of the microglia and the immune cells of the periphery. The microglia not only produces pro-inflammatory cytokine and chemokine secretion with decreased anti-inflammatory agents but also releases reactive oxygen and glutamate species [87]. Each type of cell of the innate and adaptive immune system can organize the inflammatory response within the CNS and also, the autoreactive CD4 + T cells make an important contribution in the MS.

Astrocytes, Sleep Process and Diseases
One century ago Santiago Ramón y Cajal proposed astrocytes as cells that . Astrocytes release adenosine that units to its receptor, adenosine A1 receptor, occasioning sleep and driving to total sleep [89]. Furthermore, it is known that astrocytes clean the brain during sleep situations, releasing solutes and water inside the brain cleaning it through astrocytic aquaporins 4.
Furthermore, in "in vivo" microdialysis studies have shown that amyloid β (the toxic peptide in Alzheimer's brain) increases inside the interstitial fluid during wakefulness and declined during the sleep process [90], but the declination is less in Alzheimer's patients with a drop in the cleaning brain process occurs during the sleep period, produced by astrocytes [91,92]. Moreover, the changes observed in the toxic peptide diminish during AD development [93]. So, the glymphatic pathway detect could be affected in neurodegenerative patients and others, such as bipolar disorders, chronic fatigue syndrome, MS and schizophrenic situations [94]. Furthermore, the sleep/wake cycle, modulated by astrocytes, is also altered in that diseases [95,96]. Under experience in humans, many people with suffering from these diseases present an alteration REM (Rapid Eye Movement) process during the sleep period. These data could indicate alterations in the sleep period with the affectation of the active zone of the brain that initiates the switch off the brain. In fact, the patients cannot sleep well and they fill tired during the awake period, with problems in attention, memory, spatial recognition, and so on.

Therapeutic Effects to Combat Diseases
Future therapeutics against brain diseases will develop specific drugs against reactive astrocytes and microglia activation. Study on the mechanisms that eliminate amyloid beta toxic peptide, the decrement of the phosphorylation of TAU inside the neurons, the ATP changes in the brain controlled by astrocytes and the production of metabolites, will be necessary for finding therapeutic targets in AD and in other diseases [97].
In chronic pain, drugs controlling the mechanisms of SG cells and the interaction of these cells with the neuronal body will be important to assume the relationship between astrocytes and the other cells in the sensorial ganglia and the treatment of chronic pain.
With problems in the sleep/awake cycle, we can understand the relationship between all the CNS cells. In the future, to obtain better health, brain changes in the sleep inductor proteins and the sleep/awake cycle could help to fight sleep illness. Also, the influence of astrocytes in the brain clean process will be a therapeutic approach to eliminate toxic elements detected in many illnesses, such as Aβ in Alzheimer's, Parkinson, or ELA (Sclerosis Lateral Amyotrophic) disease and many other neurodegenerative diseases in which toxic proteins are present. Moreover, altered miRNA expression profile in ALS and/or other neurodegenerative disease patients has been detected with an increase of inflammation produced by microglia and astrocytes reactivities, which there are potential mediators of neurodegenerative processes [98,99].
Promoting toxics proteins cleaning by astrocytes (as amyloid-beta) will be necessary by different mechanisms such as autophagy or ubiquitin systems.
Furthermore, in reactive astrocytes, an increase in antioxidant proteins, such as Nrf2 (Nuclear Factor Erythroid 2-related factor 2), could produce benefits for our brain. On the other hand, astrocytes can take off toxic peptides from the brain leading to reactive astrocytes and increasing, inflammation, toxic proteins and University. The photo bio modulation has been used in Parkinson's disease, depression, traumatic brain injury, and stroke with reported benefits. Medical interventions, pharmacological approach, and so on, have been used in AD, but the TIBS will be a good new technique for the future.

Conclusion
Control of all mechanisms and the understanding of the relationship between astrocytes, neurons, oligodendroglia and microglia could become the therapeutic track to some neurodegenerative disorders and also to diseases such as bipolar disorder, schizophrenia, and autistic spectrum. Thus, different strategies can be considered to bridge the gap between human disorders and astrocytes and glia intervention. Furthermore, the presence of different types of astrocytes and increases or decreases of them depending on the diseases and age should be a predominant study in the future. Hypothesis looking for the role of astrocytes in mammalian functions will be necessary and a new field in the astrocytes job in the nervous system has been opened now. That will provide a new direction for future interventions in CNS diseases.

Funding
Not applicable.

Acknowledgments
Thanks to Dr. Martin Aldasoro, Dr. Jose Mª Vila and Dr. Jose Mª Estrela to provide materials and professional writing services.

Authors' contributions
AJ designed the review, critically revised the manuscript, and corrected English in the manuscript. SKS corrected English in the manuscript. IC did experiments and interpreted the data. SLV conceived of and designed the review, drafted the manuscript and performed proofreading. All authors read and approved the final manuscript.

Conflicts of interest
All participants provided written informed consent. Participants have declared that no competing interest exists.