Neural and glial cells assist in survival (The verve of injured neurons (a single neuron tries to survive))

Neuronal life and death is controlled by glial cells [885, 332]. Nevertheless, when we speak about a brain, we imply neurons. Really, that’s the truth, but not the whole truth. Brain consists of neurons and glial cells: astrocytes, oligo-dendrocytes and microglia. It had been thought that glial cells only physically support neural networks, ensure a reinforcing cage for proper functioning of the neuronal scheme and do not themselves participate in the mental function. As a simplification, this was close to reality, but at the present, many data are not kept within so straightforward a representation. Brain activities are a coexistence of the several cell’s populations. Neurons are born, live and die within the brain. Glial cells also are born, live, die and interact with the neurons. This interaction sometimes looks like collaboration and sometimes like a fight. Neurons are also not homogenous and differ by their locations, chemical distinctions, morphology and functions. Different strains of neurons collaborate or battle as well. Some neurons excite their target cells, first of all by glutamate, and some neurons inhibit them, first of all by GABA. Correspondingly, some neurons harm their target cells and some protect them. However, this simple rule does not operate in all cases. Cells in many cases require extracellular factors that are produced by other cells in order to stay alive [1176]. Moreover, the same impact in some cases may protect cells, but in other circumstances may harm them, such as NO production [1439, 360] and microglia activation [848, 695], or the same impact influences differently on different (even close) neurons [1427]. Soon after damage, inhibitory processes, which could protect a cell, are usually declined, but this is not connected with the loss of GABA interneurons [403]. In the same way that an excitation does not always damage cells, cell protection may proceed without inhibition. What is more, excitation may sometimes protect cells.


Damage and death of brain cells provokes an immunological reaction, which is ensured by glial cells. Immune functions as phagocytosis and cytokine production have emerged 700 million years ago in starfishes and sponges [971]. Ancient immune defense mechanisms were very effective, but lacking memory function. 500 million years ago, the basic system for creating the genetic material for recombination and mutation was developed to establish variability and diversity of proteins such as immunoglobulins. NO is a factor of innate immunity in early phylogenesis, while opioid peptides – in the late phase of phylogenesis. NO was present in phagocytic cells and guaranteed an effective defense. For those ancient mechanisms, the trigger to activation is stress that in invertebrates is channeled through macrophages, while stress response in vertebrates induces activation of the hypothalamus, adrenal gland, pituitary gland, etc. More recent, opioid system is much more specific in respect to harmful impact [910, 141]. Both astrocytes and microglia are cells that provide immune surveillance in the central nervous system [824]. The role of microglia sharply differs from the role of astrocytes. Microglia comprises several percentages of cells in the brain. Under pathological conditions microglia become active and surround damaged and dead cells, like phagocytic macrophages of the immune system [384]. Microglia are activated during various neurological diseases and this has earned them a reputation as endogenous malefactors, but the activities of these cells are for the most part beneficial. becoming destructive only when they escape from the strict control normally imposed on them, that is after severe damage [1109]. The executive functions of mi-croglia can change not only in magnitude but also in quality. Depending on the magnitude of microglial reaction, on the type of stimulus and on the concurrence of other local factors, microglia can contribute to defense and repair. When damage is harsh and cellular homeostasis disrupts proper functioning, mechanisms of defense fail and microglia are involved in the establishment of brain damage [848]. However, although cells of microglia are intimately connected with inflammation, neuronal damage, infection, etc., cells of microglia, probably, also directly participate in mental activities and participation in cerebral function is determined just by their servicing neuronal damage and protection.

On the microglia membrane, a special type of Na+ channels and several K + channels are present and they are important for microglial activation. Many neuronal signals, such as ATP, NO, substance P, excitatory amino acids, or pro-inflammatory cytokines may provide the stimuli for microglial activation [305]. Particularly, as a main instrument of neuronal excitability, tetrodotoxin-sensitive Na+ channels participate in activation and phagocytosis of microglia [274]. Ca2+-dependent glutamate signaling between astrocytes and neurons is potently amplified in the presence of inflammatory microglia [119]. Astrocyres are the most abundant non-neuronal cells in mammalian brain and in humans constitute 50% of the total brain volume [260]. In the human cortex, there are 3.4 astrocytes for every neuron [885]. The processes of one astrocyte contact tens of thousands of synapses. For instance, one hippocampal astrocyte makes contact with 100,000 synapses and astrocytes themselves are functionally compartmentalized [526]. Therefore, individual astrocytes can integrate signals from numerous synapses, and signal back to multiple synapses. Glial cells regulate basic neurotransmitters, glutamate, GABA and taurine, which ensure the large share of excitatory and inhibitory transmissions and which are important for neuronal damage-protection. Cycling of neurotransmitters, ions and intercellular messengers are the basic means for interaction of glutamatergic neurons, GABAergic neurons and glia. Glia cells capture glutamate from the synaptic cleft, convert it into glutamine, which is transported into the neuron and is reconverted into the neurotransmitter molecules [1139]. Astrocytes are very sensitive to glutamate released from synaptic terminals [209]. Intracellular Ca2+ rises in glial cells and triggers glutamate release that modulates neuronal function [119]. The uptake of glutamate into astroglia is the predominant mechanism to terminate glutamatergic neurotransmission and to prevent neurotoxic extracellular glutamate concentrations [387]. Disruption of astrocytic support leads to exci-totoxic damage [512]. The assistance of glia to metabolic processes of neurons is evident, but in addition, glial cells contribute to information exchange in the brain. Certain astrocytes receive direct glutamatergic and GABAergic synap-tic innervation from neurons and respond to synaptic activity by releasing transmitters that modulate synaptic activity [675, 538, 27].

In some cases, astrocytes can enhance excitatory synaptic transmission. Thus, astrocyte-derived glutamate preferentially acts on extrasynaptic receptors, augments neuronal excitability, supports neuronal synchrony and can influence damage by release of glutamate. In other situations, astrocytes release molecules of the ATP that suppress synaptic transmission. Many other receptor types are also expressed on astrocytes, including opioid, dopamine, acetylcholine, glycine, serotonin, ^-adrenergic, and purinergic receptors; as-trocytes express also ion channels, both ligand-gated and voltage-dependent [675]. In astrocytic membranes, K + channels predominate over other ion channels and this prevents their excitability [885]. Astrocytes participate in many physiological functions of neurons. They have been implicated in dynamic regulation of neuron production, synaptic network formation, neuron electrical activity, neuronal assembles and specific neurological diseases [1012]. Glia displays the remarkable capacity to discriminate between different levels and patterns of synaptic activity [209]. Astrocytes and microglia intimately participate in neuronal sensitization not only via the release of glutamate, but by evoking changes in synaptic ion homeostasis, too [305]. In response to neuronal signals, astrocytes can signal back to neurons by releasing various neuronally active compounds, such as the excitatory neurotransmitter glutamate. This bidirectional communication system between neurons and astrocytes may lead to profound changes in neuronal excitability and synaptic transmission [209].

Cooperation of brain cells is brightly displayed during spreading depression that is characterized by rapid depolarization of both neurons and glia. The extracellular ionic shifts during spreading depression include an increase in K + , and decreases in Na+, Cl-, and Ca2+, but intracellular Ca2+ in astrocytes increases in response to membrane depolarization. Astrocytes normally extrude calcium during spreading depression, resulting in rapid recovery of the levels of extracellular Ca?+ [1362]. Astrocytes play a role in brain homeostasis, regulating the local concentrations of ions, amino-acids and other neuroac-tive substances [964, 733]. Microglia also can sense homeostatic disturbances. Neurons and glial cells recover homeostasis that was disturbed during functioning and ensure joint regulation of damage-protection. At the same time, they, probably together, control behavior. And all this coexistence is somehow converted into our identity. Processing of information is important, but not the single attribute of brain. Existence of neurons and glia between life and death turns their indifferent "calculations" into cooperative being. Therefore, interaction between physiological activities of neurons and glia is a properly established fact, but the role of astrocytes in behavior is less clear. For instance, functionally syncytial (that is electrically connected) glial cells are depolarized by elevated potassium to generate slow potential shifts that are quantitatively related to arousal levels of motivation and accompany learning [697]. It was established also that inhibition of astrocyte-specific metabolic pathways rapidly impairs vision and learning [538].

Nevertheless, physiological processes in glial cells are slower than in neurons and therefore they cannot participate in fast behavioral activity. Astro-cytes react to neural influences slowly, during a few seconds [964] and this is not compatible with the time scope of current behavioral actions. Ca2+ concentration in astrocytes may also alter in response to neuronal activity during seconds, because of Ca2+ outflow from intracellular stores [964, 538]. However, direct influence from an astrocyte to a neuron’s electrical activity may be rather rapid, since the rise time of the astrocyte-evoked slow glutamate-mediated inward current in neurons is 60 – 200 ms, and the current can be extremely large in magnitude because vesicles within astrocytes are large [526]. Responses of astrocytes to signals from the environment or blockage of metabolic pathways takes minutes [538, 27]. Development of neu-ronal damage after different impacts is also slow, minutes or tens of minutes [416, 836, 1366, 1426]. Within 2 minutes of stroke onset, neurons and glia undergo a sudden and parallel loss of membrane potential caused by failure of the Na+, K+-ATPase pump and disturbance of neuronal homeostasis[36]. The reaction to acute neural injury is a massive expansion of the microglial cell population, which peaks a few days following injury. At the same time, the initial stage of microglia activation from minutes to a few hours following injury is related to neuronal compensation, rather than to injury [695]. A characteristic time for initial microglia reactions is minutes [742, 36, 384]. This does not allow one to exclude microglial cells from consideration of their possible participation in the regulation of behavior. Whereas microglial cell bodies and main branches stay stable for hours, their evenly distributed and highly ramified processes in the brains of anesthetized animals are remarkably motile (1.5 mkm/min) [384]. Astrocytic processes also dynamically alter their apposition to synapses in response to environmental cues, although transmitters do not change their own membrane potential [27].

Current processing of information in a brain takes a fraction of second to complete. These fast-acting episodes concern the reception and recognition of signals, decision-making and actions of previously alerted brain. Reaction to unexpected signals and recollection take extended periods of time, right up to seconds and more, while reorganization of brain states, such as sleep-awareness, hunger-satiation, memory consolidation, etc. proceeds in a middle-time scale and may take minutes or more. Rapid processes in a brain are, evidently, executed by neurons, while in the slow reorganization of brain conditions, both neurons and glial cells may, in principle, participate together. Obviously, service of glial cells to neurons is not restricted only to support of neuronal electrical activity. Glia is, doubtless, capable of making a larger contribution. It is impossible to exclude the option that glial cells not only serve brain, but also participate in the slow gradual tuning of cerebral function. For example, they could participate in the sluggish recording of memory and in its rapid reproduction, all the more that astrocytes are richly equipped with the tools for reorganization of intercellular connections: gap junctions. Taking into consideration that astrocytes slowly react to neuronal activity but promptly exert an effect on neurons, they could rapidly modulate behavior in accordance with previously prepared situation. Thus, neural and glial cells agreeably interact in support of the physiological function of brain. They communicate between outer and inner environments by means of second and retrograde messengers and an exchange of ions. Let us now consider processes of survival. We will argue further its importance for mental function.

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