Disorders of human consciousness in the Tri-partite synapses

Journal Pre-proofs Disorders of Human Consciousness in the Tri-partite Synapses B. Miterauer, W. Baer PII: DOI: Reference:

S0306-9877(19)31137-5 https://doi.org/10.1016/j.mehy.2019.109523 YMEHY 109523

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Medical Hypotheses

Received Date: Revised Date: Accepted Date:

10 October 2019 4 December 2019 8 December 2019

Please cite this article as: B. Miterauer, W. Baer, Disorders of Human Consciousness in the Tri-partite Synapses, Medical Hypotheses (2019), doi: https://doi.org/10.1016/j.mehy.2019.109523

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Disorders of Human Consciousness in the Tri-partite Synapses B. Miterauera, W. Baerb aProfessor bAssociate

of Neuropsychiatry, University of Salzburg, Volitronics-Institute, Wals, Austria Professor of Information Sciences (Ret), Naval Postgraduate School, Monterey, CA, USA

Abstract Conscious Action Theory extends quantum theory to macroscopic phenomena and suggests physical correlates of consciousness occur at the intersection of external measurement signals and internally generated signals from memories that model the outside world. This physical theory predicts conscious phenomena happen at all scales and differ only by the size and complexity of material organizations involved. At the scale of the human “Brain” consciousness is predicted to happen where the processing loop of activity in the Glial network interfaces with the real world input-output processing loop of the Nuronal network. This happens at the Tripartite synapses creating an intersection plenum in biological systems that produces the experience of empty space and the objects it contains. Analysis of the transmitter-receptor strengths implementing the control and feedback between the Glial and Neuronal networks indicate imbalances can be directly related to schizophrenia, mania, epilepsy, and depression. This paper addresses three topics supporting the above mechanisms for normal consciousness functioning and its medical deviations. First we preset the architecture of a pan-psychic physical theory, which supports the hypothesis that tri-partite synapses are the location of human conscious experience. Second we discuss the inner workings of the Glial network to support long term memory and control functions corresponding to the inner feeling of the “I” self. Third, we consider the relation between psychiatric

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conditions and the balance states between the number of neuronal transmitters and astrocytic receptors.

Key Words: Physical Correlates of Consciousness, Glial-Neuronal Network Interface, Tri-partite Synapses, Conscious Action Theory, Consciousness Disorders, Schizophrenia,

1 Introduction William James [1] concluded consciousness is a process and therefore mental disorders may be caused by disturbances in the flow of activity executed in the “Brain” when interpreting sensor stimulation and producing the mental display we all experience in everyday life. An action flow model of a “Reality” that explains the conscious phenomena was initially proposed Baer [2]. Such a theory assumes “Reality” and “We” cognitive beings are most appropriately described as interacting networks of physical “Action Cycles”. Conscious phenomena are correlated with the activity happening at the interface between sensory loops gathering information from the external world and memory loops signaling expected stimulation calculated from a memory model grown to manage and control our behavior. Though such interacting loops are physically applicable to all scales from atomic to cosmological phenomena, at the human level the architecture maps quite precisely to the Astrocyte interface between the Neuronal and Glial networks happening in the tripartite synapses. We therefore hypothesize that the flow of activity surrounding the field of tripartite synapses are correlated with the consciousness phenomena and disturbances in the normal flow of these activities cause clinically significant mental disorders. Though imbalances in synapses are commonly found in mental disorders and epilepsy, here we focus on imbalances of tripartite synapses. A tripartite synapse consists

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of the presynapse and the post-synapse as the neuronal component and the astrocyte as the glial component [3]. It is experimentally well established that dysregulations and structural changes of astroglia play a key role in the pathophysiology of neuro-psychiatric disorders [4]. However, there is growing evidence that the quantum paradigm may contribute to the understanding of mental disorders [5]. A recent study emphasizes the applicability and translational implications of the 'orchestrated object reduction theory' in the context of schizophrenia discussing the relevance of quantum biology for the understanding of 'fundamental disturbances in consciousness' in this disorder [6]. How an action flow model [7], which expands quantum theory to address biological phenomena, can now produce quantitative predictions applicable to biological phenomena will be discussed in the next section. 1.1 Summary of Conscious Action Theory For over a century it has been known that it is necessary to include the interaction with the observer when constructing a physical theory of the world we live in [8]. Werner Heisenberg, one of the founders of quantum theory, suggested his theory was the physics of the system that knows the world not the world itself. We have now reached the point where the logical architecture of “systems” which know the world has been identified. The Conscious Action Theory (CAT) explaining the details of conscious experience contained in the material of events is now available [7]. CAT proposes that the appearance of the normal conscious experience happens at the interface between external sensor driven action flow and the flow from internal memory sensors. The purpose of the memory model of reality is to accurately predict the external memory flow and impose

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beneficial control changes in that flow. An abstract version of the functional processing architecture happening at the point of consciousness is shown in Figure 1.

When considering this diagram it is important to understand that it represents an action flow sequence happening at different times in the same material. At the top we see the past external sensor-effecter stimulation being processed by “m()” through action paths from the sensors through the unconscious thought process region and out through the muscle coordinator and/or sensor reset process “x()” modifies the same sensoreffectors to future material state. This path could be identified with reflex-actions implemented in the neuronal “hardware” complex which can be constructed and executed in a modern computer. Such a computer or a biological version is not conscious even though, given sufficient calculation complexity it might mimic human behavior and pass a Turing test for some period of time. Consciousness is located in the operation of the comparator function, where signals from the external input-output (I/O) stream are tapped off and compared with a similar stream arriving from memory measurements. The memory shown here contains a classic objective world model. This conscious system’s control symbol “I” imagines itself as a human with a brain. Signals from the interface arrive at I’s modeled brain and project outward into the modeled world. These signals correct the world model to what the world must have been in order to produce the measured signals. Once corrected the model updates (see arrow) itself in order to generate the future configuration of the world model, which processes a response that

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stimulates the brain model, and then outputs through the model measurement process “M()” to the comparator interface. It is critical to understand that the world model must predict the future expected response of the real world in order to generate feed-forward signals that produce effective control. Model errors leading to false predictions can lead to catastrophic behavior and death of the organism. It is beyond the scope of this paper to address the evolutionary forces that have lead to the world models currently employed by the average sane individual in our society. It is also clear that psychotic symptoms may be due to model errors and neuron pathway errors in the X(),x() and M(),m() functions in Figure 1. In this paper we specifically address psychotic conditions that relate to the consciousness experience we hypothesize happens in the comparator function. Before making the case that external sensor-effecter loop can be identified with the I/O function of the Neuron-network while the internal memory loop can be identified with the Glial-network which logically locates consciousness phenomena in the comparator interface we will parameterize the comparator function using quantum nomenclature. This will allow quantitative analysis of the conscious phenomena and its disorders. Consider Figure 2 in which a comparator is shown that operates as a two way half silvered mirror which transmits and reflects feedback signals from two directions.

Utilizing quantum nomenclature the incoming signals are identified with the neuronal and glial data streams which are modulated by backward propagating Schrödinger wave functions “Ψex and Ψ*in” respectively. These interact at the comparator, which mixes reflected and transmitted signals. When mathematically

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combined in the comparator using a quantum measurement action operator “A”, the action “A(x,t)” is produced as a function of the space location vector “x” and time “t” of the comparator event. A(x,t) = Ψ*in •A• Ψex (1) According to classic physics the action, as a function of space and time, represents observable experiences we encounter in our everyday lives. Thus the comparator implements the mathematical operation that represents the happening of physical correlates of consciousness. It is very important to note that in neurophysiologic applications the space vector “x” is the name or address of the neuro-glial complex implementing the comparator function and “t” is the internal coordination time in the observer’s brain. It is not the space and time of a 2nd-person observing that brain from the outside. The fraction of the signals ((ar+bt) ∙ Ψex , (br+at) ∙Ψ*in) which are reflected and transmitted in the comparator function is given by the numerical amplitude values “ar, at” and br, bt”. The strength of transmitted vs reflected signals are symptomatic of the psychic relation between the internal and external world. There parameters are analog and represent a nearly continuous gradations of psychic conditions as their values change. In subsequent sections the characteristics of the comparator will be identified with the operations in the tripartite synapses. The number of Neuronal and Glial receptors available to accept respective Neuronal and Glial transmitters sent will determine the various mind body interaction states. Depending upon the reflection and transmission value characteristics of the comparator the following are a sample of conditions that would be experienced.

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Table 1. Sample transmission and reflection coefficients ar at br bt 1 0 1 0

.5

.5

.5

.5

.25

.75

.25

.75

.25

.25

.75

.75

0

0

1

1

description. -no interaction between internal and external signals -balanced mixing of internal and external signals -self correcting behavior, Freudian slips -output control dominated by internal expectations -reflex thought reaction to external stimulation

In the first example the input signal back to the psyche’s model of reality will simply be a reflection of what was expected while no correction penetrates to the output muscles control data stream. The Zex equals Z`ex and Zin equals Z`in. Such a state would be identified with a lucid dreamer who firmly believes his experience is real while at the same time allows his body to operate on automatic reflex control that looks like sleeping body to external observers in the rest of the universe. In the second case, an exact balance of internal and external signals produces an equal mixture of external sensations augmented by internal recognition signals. This is the normal operating mode of the human psyche. In this mode the psyche experiences the sensations of qualia from external stimulation registered with the memory recall sensations that identify the qualia as recognized objects. Such objects are theoretical entities produced by the cultural and species dependent model believed and installed in

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the psyche. One would expect a fairly wide range of values fall within the bounds of normal operation in which the psyche accepts some level of external information in order to update and correct its internal model while at the same time transmitting a limited and appropriate level of commands. Small deviations from “.5” represent personality differences. In example three large deviations dominating the output signal “.75 ∙Ψ*in“ is balanced by an equally dominating memory model update signal “.75∙Ψin“ that, under normal circumstance, would quickly correct the expectation command and the behavior would be ascribed to a temporary glitch, perhaps a Freudian slip, or anger dominated temporary insanity. Self correcting imbalances are usually considered to be personality characteristics. Psychotic behavior is evident when the imbalance reaches the values shown in the fourth example. Here the memory generated “.75∙Ψ*in” signal dominates and the output explanation, muscle control that also determines speech is generated not by behavior appropriate to external information but rather the internal expectations. Because these expectations are no longer controlled by the weak update signals “.25∙Ψin“ dominant output behavior would not be corrected leading to various forms of psychotic behavior. In the extreme case shown in example five the behavior is completely dominated by memory-model based output. As long as the model is accurate and remains in perfect synch with the external world, the system stays in equilibrium and its behavior could still be appropriate as judged by the external world. For a short period an individual can navigate a dark room simply from memory, but without optical or tactile feedback the

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memory model will soon loose synch and crash its body into things. Without feedback a system would simply do what it does without any adjustment for the consequences. The implementation of a conscious experience in a physical system has necessarily been developed in a pan-psychic theory of physics using graphic language and mathematical nomenclature that applies to consciousness processes happening in all material at all scales. To paraphrase Nagel [9] - the conscious experience is what its like to be material and all parts of the universe exhibit this characteristic. We will now narrow our discussion to the specific activities happening in the human brain’s interface between the glial and neuronal networks.

2 The Glial Network 2.1 Integration in neuronal-glial circuits by gap junctions Gap junction channels formed by connexins mediate the propagation of intercellular calcium waves. In these cellular networks astrocytes exchange molecules and permit bidirectional diffusion of nutrients, ions etc.. The gating of gap junction channels in the brain is regulated dynamically [10]. Gap junctions are capable to vary their conductance [11], their subunit composition, the number of cell contacts and show activity dependent plasticity [12]. Most gap junctions in the brain are located between glial cells, where coupling strength can be very high, In particular, astrocytes are interconnected via gap junctions, which mainly consist of connexin (Cx) 43 and Cx 30. The intensive Astroglial coupling builds an Astroglial network. Astrocyte signaling occurs mainly through the generation of intercellular calcium waves generated spontaneously in the endoplasmic reticulum and/ or in response to neuronal activity. Importantly, gap junctions are not only formed

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between astrocytes, but also between astrocytic processes, called reflexive gap junctions [13]. In a biophysically constrained computational model it has been shown that astrocytes can modulate the fast neuronal network activity through their slow intercellular calcium wave speed and amplitude and possibly cause oscillatory imbalances observed in various brain diseases such as Alzheimer’s disease, Parkinson’s disease, epilepsy and depression [14]. There is evidence that feed-forward and feed-back loops execute not only in tripartite synapses but also in the integrated neuro-glial network. Each astrocyte defines a synaptic island and neurons in a particular synaptic island are connected in a feed-forward manner to the next island. Feed-forward control is a process adjusting behavior in a continuative way. Feed-forward takes place when an equilibrium state is disrupted and the system has to automatically retrieve the homeostatic stable state. The role of feed-forward in the modeling of mental architecture got a new impulse by recognizing the importance of feed-forward connections in the brain [15]. The high diversity of astroglial receptors, their spatial location, and the spatiotemporal properties of the synaptic-dependent Ca2+ signals enable a single astrocyte to detect processes and decode the activity of a variety of synapses that can provide distinct feedback and feed-forward modulation [16]. Local feedback excitation mediated by glutamate is provided by astrocytes as a source of neuronal activation that may be critical in controlling synchronous depolarization of groups of neurons. In parallel, by providing distant feed forward actions mediated by purines, the astrocyte suppresses synaptic transmission. Astrocytes stipulate balanced excitation and inhibition mediated by these two distinct transmitter systems in a coordinated manner. "Any

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displacement of this equilibrium between excitation and inhibition has the potential to lead to disorders of the nervous system." [17] According to Pereira and Furlan [18] a realistic modeling of neuron-astroglial network should consider small waves generated in a population of billions of astrocyte micro-domains that communicate and interfere with each other and with neuronal electromagnetic fields, generating a large wave that is proposed to correspond to actual conscious states and processes. In a philosophical perspective these authors speak of a "Double-Aspect-Monism", since neuro-astroglial calcium waves and their conscious information contents are thought to be two aspects of the same underlying reality that may be described as a quantum entanglement of calcium waves. Experimental findings indicate that signaling between neurons and astrocytes runs bi-directionally in tripartite synapses. A tripartite synapse consists of the presynapse and the postsynapse as the neuronal component and the astrocyte as the glial component [3]. As outlined in Figure 3 neurotransmitters(NT) released from the pre-synapse activate both the postsynaptic receptors(poR) and the astrocytic receptors(acR).

The activation of acR by NT increases the Ca2+ concentration in the Astrocyte and leads to the production of gliotransmitters(GT), which occupy extrasynaptic receptors(esR) and feed back to pre-synaptic receptors(psR). Gap junctions(GJ) and hemichannels(HC) interconnect astrocytes building the glial network. Assuming gap junctions are bi-directional communication channels then the forward flow of substance and wave can be recognized as a feed-forward while the back flow a feed-back function that, if considered separately, would implement action loops

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which we have already described in the tripartite Synapses. This consideration suggests that the neuro-glial network represents a biological substrate for interacting action cycles as required for the appearance of conscious phenomena in the Conscious Action Theory presented above. 2.2 Interacting consciousness feedback loops in tripartite synapses An individual element in the field of tripartite synapses provides an extremely small contribution to the total experience of a human. The mapping between what is seen or experienced and individual happenings at a specific synapse generates a conscious observable if the observer’s attention is focused on the specific perceptive modality controlled by the Astrocyte. The parallel optic channels providing a parallel flow are the most obvious example of what we pay attention to. Here hallucinations or the absence of normal sight may be linked to Astrocyte control of optical channels. However a large amount of processing happens unconsciously along the hierarchy not customarily associated with external sensory display but moods and behavior attributes. It is imbalances throughout these more general locations that contribute to medically salient psychotic phenomena. Imbalances found in individual synapses can provide great insight into the global behavior of the organism. Toward this end we have mapped the flow of action represented as quantum disturbances in Figure 1 and 2 onto the biology of an Astrocyte Syncytium shown in Figure 4 below. Here the logarithm function is used to convert wave nomenclature of quantum theory (Z0ex • Ψex ) into classic particle language in order to correspond to the more conventional visualizations of pulses, transmitters, and receivers conceived as small objects. Here the general structure of neuronal loop is shown flowing from external

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reality through a neuronal synapse and back to the outside, while a similar action flow is shown flowing through the Glial network at the bottom. Between these two are two information transfer feedback loops interacting at the functional comparator operation located in the Astrocyte. No attempt is made to define the physiology inside the Astrocyte responsible for implementing the comparator operation.

The perception of neural input signal is divided into empty space Z0ex and objective content Ψex. The Glial Receptor(GR) and Transmitter(GT) strength are set by monitoring the updated expectation signal (SE) from the Glial Network. The value of GT modified by the external Comparator output “Cex= Cex(SE, Aex)” sets the presynaptic action strength “SNT =SNT(Nex,GT)”of the pre-synapse which controls the number of neural transmitters “NT = NT(SNT )“ produced in the gap. Some fraction of the neuronal transmitters “(1-%N) •NT” are absorbed in the postsynapse, which becomes the neuron output pulse signal Nex[q] of the neuron address “q”, while some fraction becomes the number available to stimulate the Astrocyte Glia Receptors. The Astrocyte input signal is therefore functionally described by independent parameters shown in the following computer language expression for a process executed by a machine, Aex = Aex( %N, SE, Nex, Aex); The complexity of this function hides the dependent values of GR, GT, NT as well as any implementation structure of the Comparator or other pertinent housekeeping

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function of the biological cells involved. Aex is the external world monitor signal absorbed by the Astrocyte. An analogous flow mechanism processes signals (Calcium Waves) from the Glia network and produces the expected external world signal SE, which comes from the External World Model implemented internally in the Glial network. At our current state of knowledge this Aex() function is not known with sufficient accuracy to produce detailed numerical predictions. However qualitative analysis will allow us to identify action flow strengths with observed behavior that give us insight into the cause of medical conditions. If the actual Aex signal exactly matches the updated expected action monitor signal the comparator mechanism produces a null difference. In this case the Glia Transmitters and Receptors had been correctly configured to modify the incoming neuronal pulse strength and produce Neuronal Transmitter monitor strengths NT•%N that will match Glial Receptor configuration. This is identified with quiescent operation. Without measuring Nex we cannot specify what the conscious being will experience, but we can state that such a configurations will produce an experience predicted by the internal Model of Reality. Hence conscious sensations contain no surprises and are associated with a kind of comfort and satisfaction when things are happening exactly as we expect. Small deviations produce small updates which instantly (within a cycle period) correct for unpredicted sensor stimulation and track the incoming data stream by real time updates to the Model of Reality. This situation corresponds to normal human operation where manageable change is experienced and appropriate actions are sent back to the external reality.

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If the Comparator output is other than at the small linearly correctible levels the match between the updated and therefore expected next Neuronal Transmitter Monitor strengths will not be tracked. Temporary shocks are normal but with continued disturbances various symptoms of psychotic behavior will appear. A detailed explanation of such behavior will be provided in the following sections. A summary list of symptoms and their associated tripartite synapse configuration states will be listed below. Depression – When GR is substantially larger than normal NT•%N neuronal transmitter flux is reduced and external world control is slowed producing lethargy, sleep, and failure to adequately respond to normal stimulation Manic – When GR is substantially smaller than normal NT•%N neuronal transmitter flux is reduced and external world control is slowed producing exaggerated response, rapid activity, and inappropriate over reaction to normal stimulation. Epilepsy – When GT rises substantially above normal levels excessive Neuronal Transmitter production produces manic symptoms. If additionally GR reduction does not produce adequate Aex damping strengths a runaway amplification loop will produce excessive and uncontrolled neuronal firing. Schizophrenia – The Comparator operation executed in the astrocytes acts as a general interface between the external and internal action flow. Update and reality checks depend both on the number and proper functioning of this interface. If both GR and GT strengths are substantially reduced the influence between the two networks is also diminished. This means the

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self stimulation of the Model of Reality is no longer controlled by reality checks and thoughts and dreams generated in the Glial Net will be returned as though real. Hallucinations, voices , and other symptoms of Schizophrenia are explained by failures in selective interface cells. A field of astrocytes control channels of Neuron bundles. Thus the general optic background world may be processed by functioning astrocytes but channels of imbalanced cells will allow thoughts to break through unfiltered and merged into the perceptive display. Extreme detachment may produce a catatonic state. When such disruption reaches neuronal channels that control housekeeping functions the result may be death accompanied by a period of total internal self stimulation. It should be noted that the architecture is independent of the actual Model of Reality grown by any cognitive being. How any individual perceives the world will depend upon the details of that model growth. Deep beliefs are incorporated in early stages of such growth and visualization of such beliefs would be expected to reappear as the cells maintaining the action flow channels disintegrate. Recovery from near death experiences or deep meditation would allow the formation of memories which could be recalled or taught to other individuals. The diversity of religious teachings as well as the convergence of their deepest truths can therefore be tied back to their origin in our common physiology.

3 Mechanisms of Psychiatric Disorders

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In this section we describe how the disturbances which arise in the combined neuro-glial network, quantitatively identified as imbalances in the transmission and reflection parameters in our model of physical correlates of consciousness, may lead to depression, mania, schizophrenia, and epilepsy. Generally, psychiatric diseases were thought to result from gross imbalances of the transmission and connectivity in neural circuits [19]. Our hypothesis is that dis-regulations and dysfunctions of feed forwardfeedback loops processed by bidirectional propagation of calcium waves in neuro-glial networks may underlie the phenomenology of mental disorders and epilepsy. The effects of over expression (depression), under expression (mania) and non-functional (schizophrenia) astroglial receptors on the propagation of calcium waves in neuro-glial networks are basically the following: 3.1 Depression The basic symptoms of major depression are depressed mood and loss of interest or pleasure [20]. Figure 5 shows a model of an imbalanced tripartite synapse responsible for the pathophysiology of major depression. Gap junctions(GJ) in the astroglial network and astrocytic receptors(acR) are over expressed and acR cannot be activated by neurotransmitters(NT) in real time. This leads to a diminished calcium concentration and production of gliotransmitters(GT) in the astrocyte causing a protracted negative feedback on pre-synaptic receptors(psR) and extrasynaptic receptors(esR), so that neurotransmission is delayed. In parallel, the synaptic activation of the astroglial network is protracted and the propagation of calcium(Ca2+) waves is slowed down. Depressive patients exhibit lower power in delta/slow wave activity than the normal population [21]. The model of delayed information processing in tripartite synapses could explain typical

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symptoms of depression such as feelings of insufficiency and disturbances of circadian rhythms [22]. Since neuronal activity is not processed in time, patients with major depression may be "frozen" in fixed conscious states observed in retarded thinking, speaking and motor behavior. Alterations in expression of connexins(Cx), gap junction function and hemichannel activity may play an important role in the pathophysiology of major depression. Decrease of Cx 43 was found in the orbitofrontal cortex and Cx43/Cx30 in the locus coeruleus, but an increase in the cerebellum. Importantly, Quesseveur and coworkers [23] identified in a stress model of depression an increase of phosphorylation of Cx43 and found that the therapeutic effects of antidepressant drugs exert a functional inactivation of Cx43. Although typical receptors for neurotransmission have been identified on the astrocytic membrane [24], dis-regulations of the expression of astrocytic receptors are as yet not elucidated in depression. However, up-regulation of astrocytic receptor expression are found in Alzheimer's disease [25] and Parkinson's disease [26]. Importantly, in animal models of chronic stress adenosine A2A receptors are upregulated associated with emotional disturbances as observed in depression [27].

Basically, synaptic dysfunctions in the pathogenesis of depression are supported by various experimental findings. Although most investigations focus exclusively on the neuronal system, there is growing evidence that the glial cell system, especially astrocytes, play a significant role in the pathophysiology of depression [14]. Reviewing the pertinent literature Rial and colleagues suggest that depression is a glia-based synaptic dysfunction [27]. Basically, in major depressive disorder degeneration of

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astrocytes and decreased numbers are found that may lead to "misbalance" in neurotransmission and aberrant synaptic connectivity [28]. Decrease of astroglial cells and GFAP (glail fibrillary acid protein) expression identified in brains with major depression is paralleled with down-regulation of astroglia-specific proteins, especially those important for astroglial homeostasis [29]. In animal models chronic stress downregulated the expression of astroglia specific connexin 43, which was reflected by a decreased dye coupling between astrocytes in the prefrontal cortex [30]. Importantly, the causal role for astroglia associated pathological changes in depression was shown in experiments with direct ablation of astroglial cells from the medial frontal cortex in mice resulting in the emergence of depressive phenotype similar to that induced by chronic stress [31]. Imaging connectomics in brains with affective and psychotic pathology has found striking evidence for disease connectomic "fingerprints" that are disrupted across distinct forms of pathology and appear to scale as a function of illness severity [32]. However, in our model of the pathophysiology of affective disorders the connectom may in short depressive episodes not significantly be affected [33], since it is focused on dysfunctions of astroglial receptors and gap junctions and not on astrodegeneration or loss of these cells. In a chronic course of the illness, a loss of glial cells occurs leading to disconnections in the glial-neuronal networks and an aggravation of the symptoms. 3.2 Mania The symptoms of a manic episode are inflated self-esteem or grandiosity, decreased need for sleep, pressure to keep talking, flight of ideas, distractibility, increase of goal directed activity and excessive involvement in pleasurable activities [20] whereas synaptic information processing in depression is protracted, in a manic state inverse mechanisms

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shorten information processing. As outlined in Figure 6, the reduced number of gap junctions(GJ) in the astroglial network and the under-expression of astrocytic receptors(asR) cannot exert a balancing function in tripartite synapses. A surplus of neurotransmitters(NT) relative to the under-expressed asR leads to a flooding of acR with NT. The hyper-activation of acR causes an increased Ca2+ concentration and production of gli0transmitters(GT) in the astrocyte leading to a shortened feedback on the presynaptic(psR), postsynaptic(poR) and extrasynaptic(esR) receptors. This hyperactivation causes a rapid neuro-transmission. Underexpressed astroglial receptors become flooded with neurotransmitters leading to shortened synaptic information processing and acceleration of the calcium wave propagation in neuro-glial networks. Rapid change of attention is typical, called manic irritability [34]. Although the underexpression of GJ may down-regulate the expression of acR, an acceleration of calcium wave propagation in the neuro-astroglial networks occurs, because of an increase of Ca2+ concentration. According to Mellerup and Kristensen [35] re-entry may be faster in mania, what the repetitive, recursive signaling concerns generating a conscious state faster than usual. Reentry is a process of ongoing parallel and recursive signaling between separate neuronal groups along parallel fibers, which link these groups anatomically [36]. The fastening of feedback loops in tripartite synapses is in some aspects comparable to the hypothesis of dysfunction in reentry in neuronal networks. Basically, rapid cycles in tripartite synapses could be explanatory of manic distractibility, flight of ideas, over activity and over activity of biorhythms, such as insomnia. Moreover, mania may involve radical acceleration and radical asynchrony that

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result in an instantaneous existence [37]. Rapid feedback loops in tripartite synapses may underlie this time experience. Admittedly, excessive neurotransmission caused by the underexpression of acR is yet not identified but relevant studies indicate excessive dopaminergic activity in brains with mania or bipolar disorder [38]. 3.3 Schizophrenia: Schizophrenia is a chronic devastating mental disorder. The basic symptoms are delusions and hallucinations, thought disorder, catatonic (motoric) symptoms, and affective flattening [20]. Since patients with schizophrenia are unable to distinguish between his/her own thoughts and perceptions in the environment, delusions and hallucinations may reflect the confusion about the loss of boundaries between the self and the others [39]. The pathogenesis of schizophrenia is still unknown, but existing, mainly "neuro-centric" models may be in part explanatory [40]. In the present study we focus on the key role of glial cells in the pathophysiology of schizophrenia [41] supported by convincing experimental evidence [42]. Our model of schizophrenia is based on unbalanced astroglial-synapse interactions caused by non-functional astroglial receptors leading to an unconstrained synaptic flux so that astroglia loses their modulation function in tripartite synapses [43][44]. Figure 7 outlines an unbalanced tripartite synapse in schizophrenia. Non-functional astrocytic receptors(acR)(crosses) cannot be activated by neurotransmitters(NT). Therefore, calcium (Ca2+) concentration and Gliotransmitter (GT) production is not activated by NT leading to an unconstrained neurotransmission. Hence, GT cannot exert a feedback on presynaptic (psR) and extrasynaptic (esR) receptors. A flooding of postsynaptic receptors (poR) by NT is the consequence. If the

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degeneration of glia progresses, a loss of gap junctions(GJ) occurs. Since the flux of neurotransmission cannot be modulated by astroglia, a gap between the sensory information processing in the neuronal system and the "inner" astroglial network responsible for incoherent thoughts, delusions and affective flattening exists [43]. Because the calcium concentration in the astrocyte does not become activated by NTs, the propagation of calcium waves in the astroglial network is severely impaired. Only spontaneous intracellular calcium oscillations may exert some effects. Importantly, according to Lidow [45] altered calcium signaling may constitute the central unifying molecular pathology in schizophrenia. Disturbances of neuronal synchrony in the gamma frequency band (30-100Hz) as a major pathophysiological feature of schizophrenia is experimentally well established. These synchrony deficits that may underlie the failure of the brain to integrate information may be responsible for many symptoms and deficits of schizophrenia [46]. Although schizophrenia is a chronic progressive devastating process basically caused by the degeneration of astroglia [4], in the first stage of the illness delusions and hallucinations prevail. In this stage the neuronal network may not be significantly affected. We suggest that in delusions the brain may work holistically not schizophrenically [47]. Typical are delusions of subjective universality such as "I am the universe". Importantly, Bernstein and colleagues [41] see in the pathophysiological model of schizophrenia here proposed the first cause-effect model, since the main symptoms of schizophrenia can be deduced from the pathophysiological mechanisms. As discussed in section 1 when reality check interactions between the neuronal Input/output action loop is inhibited the internal model of reality, which is physically

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controlled by the bigger Self-process becomes the unchallenged "Reality" the patients believes to be living in. Effectively such a state can be described as a "lucid dream" in which the "I" believes he or she is awake but is actually interacting with the output of the reality model held in memory. However, if astroglial degeneration significantly progresses, the astroglial domain organization disintegrates [43]. This leads to instability of the first-person perspective, which threatens the basic experience of being selfcoinciding and a persisting subject of awareness [48]. These alterations may affect the feeling of being a unique individual [49]. 3.4 Epilepsy: Epileptic seizures show a common feature: a breakdown in the mechanisms that normally constrain neuronal activation [50]. In addition to the various recognized findings in the neuronal system there is growing evidence that dysfunctional astrocytes are crucial players in epilepsy [51], [52]. Calcium signaling is able to cause hyper-excitability either by direct modulation of neuronal activity or indirectly through calcium dependent gliotransmission [53]. The enhanced glial calcium signaling can exert a causative role in a generation of epileptiform seizures [19]. Neuronal paroxysmal depolarization shifts result from massive calcium-dependent release of glutamate from astroglial [54]. Here we focus on imbalanced tripartite synapses in epilepsy [22][55]. Imbalanced tripartite synapses may be responsible for the pathophysiology of epilepsy based on imbalance between hyperactivated glutamatergic and hyperactivated GABAergic tripartite synapses. Figure 8 outlines a hyper-activated glutamatergic synapse. Glutamate (GLU) is excessively released from the hyper-activated presynapse (prs) flooding both postsynaptic receptors (por) and Astroglial receptors (acr).

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4 Discussion and Conclusions 4.1 Testing our Biologic Model Novel techniques such as optogenetics combined with imaging techniques and chemo-genetics [52] may enable the counting of astrocytic receptors in tripartite synapses matched with normal brains. In addition, computer simulations may further elucidate the model proposed, since glio-pathologic events are described as a cause-and-effect relationship [4] [57]. Mahdavi et. al. developed an extended mathematical model of an imbalanced tripartite synapse based on our model of the pathophysiology of schizophrenia [58]. It was formally shown that the lack of glutamatergic feedback from astrocytes caused by non-functional astrocytic receptors and increased nitric monoxide from the postsynaptic neuron lead to unconstrained release of glutamate by the presynaptic terminal. 4.2 Treatment options Once the cause of clinical maladies has been correlated with equilibrium disturbances in the bidirectional substance flow occurring in the glia-neuronal network interface targeted treatment options and or treatment research can be identified. Concerning schizophrenia we recently proposed the substitution of glial binding proteins that may balance synaptic information processing in schizophrenia, since these proteins exert a modulatory function comparable to astrocytic receptors.

4.3 Summary Psychotic symptoms are by definition disorders in mental functions required to generate conscious behavior. Diagnosis and treatments have been invented with

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considerable success by treating the brain and its consciousness function as a black box, without understanding the mechanisms producing conscious behavior. According to Conscious Action Theory (CAT), a cyclic flow incorporates a level of consciousness while linear segments, which have a beginning and end, only contribute to the consciousness of the larger cycles in which they are imbedded. They are not in themselves conscious. The Panpsychic approach of CAT, an extension of quantum theory, proposes that the flow of activity produces objective sensation at all levels of structural complexity. At the human level the functional analogy between interacting action cycles [59] and the flow or expression of chemical components suggests that: 1) Human consciousness can be correlated with operations of tripartite synapses 2) Disruption of operations at such sites is the cause of many clinical disorders. The understanding of the consciousness mechanism derived from physics investigations is expected to encourage research into the Astrocyte interfaces between the neuronal and glial networks with the goal of improving the treatment of mental disorders. Conflict of interest none References [1] William J. Chapter X. The Consciousness of Self. The Principles of Psychology 1955; Vol I and II Dover [2] Baer W. Introduction to the Physics of Consciousness. Journal of Consciousness Studies 2010; 17, No. 3–4; 165–91 [3] Araque, A., Parpura, V., Sanzgiri, R. P., Haydon, P. G. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999; 22; 208-215

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[4] Verkhratsky A., Rodriguez J. J., Steardo L. Astrogliopathology: a central element of neuropsyhiatric disaeses? Neuroscientist 2014; 20; 576-588 [5] Malik A., Lindesay J. Quantum Physics: Relevance to Psychiatry. NeuroQuantology 2009; 7(2); 314-317 DOI: 10.14704/nq.2009.7.2.233 [6] Venkatasubramanian G. Understanding Schizophrenia as a disorder of consciousness, Clin Psychopharmacol Neurosci 2015; 13(1); 36-47 [7] Baer W. Conscious Action Theory: an introduction to the event oriented world view, Routledge Press (2020), ISBN: 978-1-138-66746-4 (hbk) [8] Baer W. On the Necessity of Including the Observer in Physical Theory, Cosmos and History: The Journal of Natural and Social Philosophy 2015; 11(2) URL http://www.cosmosandhistory.org/index.php/journal/article/viewFile/492/825 [9] Nagel, T. What It Is Like to Be a Bat, Philosophical Review 1974; 93; 435–450 [10] Giaume C., McCarthy K. D.Control of gap-junctional communication in astrocytic networks. Trends Neurosci 1996; 19; 319-325 [11] Yang X. D., Korn H., Faber D. S. Long-term potentiation of electronic coupling at mixed synapses, Nature 1990; 348(6301); 542-545 [12] Gebicke-Haerter P. J. Engram formation in psychiatric disorders, Frontiers in Neuroscience 2017; 8(8); 118 DOI:10.3389/fnins.2014.00118 [13] Schipke C. G., Kettenmann H., Astrocyte responses to neuronal activity, Glia 2004; 47; 226-232 [14] Kozachkov L., Michmizos K. P., The causal role of astrocytes in slow-wave rhythmogensis: a computational modeling study. 2017; arXiv:1702.03993 (qbio.NC )

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[15] Basso D., Belardinelli M., The role of the feed-forward paradigm in cognitive psychology. Cogn Process 2006; 7, 73-88 [16] Araque A., Carmignoto G., Haydon PG., et al., Gliotransmitters travel in time and space. Neuron 2014; 81, 728-739 [17] Fellin T., Pascual O., Haydon P. G., Astrocytes coordinate synaptic networks: balanced excitation and inhibition, Physiology 2006; 21,208-215 [18] Pereira A. Jr., Furlan F. A., Astrocytes and human cognition: modeling information integration and modulation of neuronal activity, Prog Neurobiology 2010; 92,405-420 [19] Nedergaard M., Rodriguez J. J., Verkhratsky A., Glial calcium and diseases of the nervous system, Cell Calcium 2010; 47; 140-149. [20] American Psychiatric Association: Diagnostic and statistical manual of mental disorders 2013; 5th ed. ; Washington DC. [21] Meerwijk E. L., Ford J. M., Weiss S. J. Resting state EEG delta power is associated with psychological pain in adults with a history of depression, Biological Psychology 2015; 105;106-114. [22] Mitterauer B. J., Balancing and imbalancing of astrocytic receptors in tripartite synapses. Common pathophysiological model of mental disorders and epilepsy, Medical Hypotheses 2015; 84; 315-320 [23] Quesseveur G,, Portal B., Basic J. A., et al., Attenuated levels of hippocampal connexin 43 and its phosphorylation correlate with antidepressant and anxiolyticlike activation in mice, Frontiers in Cellular Neuroscience 2015; 9;490.

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[24] Kettenman,H. and Zorec,R., Release of gliotransmitters and transmitter receptors in astrocytes.In: Kettenmann,H., and Ransom,BR.(Eds.) Neuroglia 2013; Oxford University Press; 197-211 [25] Yu W., Mechavar N., Kratic S., et al., Upregulation of astrocytic Alpha 7 nicotinic receptors in Alzheimer's disease brain- possibly relevant to amyloid pathology. Molecular Neurodegeneration 2012; 7 article number 07. https://doi.org/10.1186/1750-1326-7-S1-O7 [26] Ishida Y., Nagai A., Kobayashi S., Kim S. U., Upregulation of protease-activated receptor.1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase, J Neuropathology and Experimental Neurology 2006; 65; 66-77 [27] Rial D., Lemos C., Pinheiro H., et al., Depression as a glial-based synaptic dysfunction, Frontiers Cellular Neuroscience 2015; 9; 521, https://doi.org/10.3389/fncel.2015.00521 [28] Peng L., Verkhratsky A., Gu L., Li B., Targeting astrocytes in major depression. Expert Rev Neurther 2015; 15,1299-1306 [29] Choundary PV., Molnar M., Evans SJ., et al., Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102, 15653-15658 [30] Sun JD., Liu Y., Yuan YH., et al., Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats. Neuro psychopharmacology 2012; 371305-1320

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[31] Banasr M., Duman RS., Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 2008; 64,863-870 [32] Baker JT., Dillon DG., Patrick LM., et al., Functional connectomics of affective and psychotic pathology. PNAS 2019; 116,9050-9059 [33]Rajkowska G., Stockmeier CA. Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr Drug Targets 2013; 14, 12251236 [34] Mitterauer B. J., Psychobiological model of bipolar disorder: based on imbalances of glial-neuronal information processing, Open Journal of Medical Psychology 2018; 7; 91- 110 [35] Mellerup E., Kristensen F., Mania as a dysfunction of reentry: application of Edelman's and Tononi's hypothesis for consciousness to a psychiatric disorder. In: Kapur,S.and Lecrubier,Y.(Eds.),. Dopamine in the Pathophysiology and treatment of schizophrenia. 2004; Martin Dunitz, London, 177-205 [36] Edelman C. M., Tononi C. A., A universe of consciousness 2000; Basic Books, New York [37] Moskalewicz,M.and Schwartz,MA.(2018) Temporal experience in mania.Phenomenology and the Cognitive Science 3,1-14. [38] Berk,M.,Dodd,S,Kauer-Sant'Anna,M.,et al.(2007)Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder.Acta Psychiatr Scand 116,41-49 [39] Hales R.E., Yudofsky S. C., Talbott J. A., The American Psychiatric Press Textbook of Psychiatry 1999; The American Psychiatric Press, Washington DC

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[40] Owen M. J., Sawa A., Mortensen P.B., Schizophrenia, The Lanzet 2016; 388;86-97. [41] Bernstein H. G., Steiner J., Guest P. C.,et al.. Glia cells are key players in schizophrenia: insights and concepts of therapy, Schizophrenia Research 2015; 161; 4-18. [42] Verkhratsky A., Steardo L., Peng L., Parpura V., Astroglia, glutamatergic transmission and psychiatric diseases. In:Schousboe,A.and Sonnewald,U.(Eds.). The Glutamate/GABA Cycle.Advances in Neurobiology 2016; Springer, 307-326. [43] Mitterauer B. J., Pathophysiology of schizophrenia:based on impaired glialneuronal interactions, Open Journal of Medical Psychology 2014; 3; 126-140 [44] Mitterauer B. J., Disintegration of the Astroglial domain organization may underlie the loss of reality comprehension in schizophrenia: a hypothetical model. Open Journal of Medical Psychology 2019; 8; 15-35 [45] Lidow M.S., Calcium signaling dysfunction in schizophrenia: a unifying approach, Brain Res Brain Res Rev 2003; 43;70-84 [46] Woo T. W., Spencer K., McCarly R.M., Gamma oscillation deficits and the onset and early progression of schizophrenia, Harv Rev Psychiatry 2010; 18;173-189 [47] Mitterauer B., Das holophrene Syndrom als Modell. Biokybernetik und Psychopathologie 1983; Springer, Vienna, ISBN-13: 978-3211817605 [48] Parnas J., Henriksen M. G., Disordered Self in the schizophrenia spectrum: a clinical research perspective, Harv Rev Psychiatry 2014; 22; 251-265 [49] Giersch A., Mishara A., Is schizophrenia a disorder of consciousness? experimental and phenomenological support for anomalous unconscious processing, Front Psychol 2017; 8;1659. http://doi.10.3389/fpsyg.2017.01659

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[50] Eisenstein M., Unrestrained excitement, Nature 2014; 511; 55-56 [51] Coulter D. A., Steinhäuser C., Role of astrocytes in epilepsy, Cold Spring Harb Perspect Med. 2015; 25(3); a022434, Doi.10.1101/cshperspect.a022434 [52] Losi,G., Cammarota,M.,Carmignoto,G.(2012) The role of astroglia in the epileptic brain. Front Pharmacol.Http://doi.103389/fphar201200132 [53] Steinlein O.K., Calcium signaling and epilepsy, Cell Tissue Res. 2014; 357; 385-393 [54] Tian G.F., Hooman A., Takahiro T., et al., An astrocytic basis of epilepsy. Nat Med. 2005; 11; 973-981 [55] Binder D. K., Steinhäuser C., Role of astrocyte dysfunction in epilepsy, Neuroscience and Biobehavioral Psychology 2017; http://dx.doi.org/10.016/B978-0-12-809324-5-00071-7 [56] Mitterauer B. J., Imbalances of tripartite synapses responsible for the pathophysiology of mental disorders and epilepsy. J. Neurology and Neuromedicine 2018; 3; 57-63 [57] Robel S., Sontheimer H., Glia as drivers of abnormal neuronal activity. Nature Neuroscience 2016; 19; 28-33 [58] Mahdavi A., Bahrami F., Janahmadi M., Analysis of impaired LTP in schizophrenia using an extended mathematical model of a tripartite synapse. Proceedings of the 22nd Iranian Conference on Biomedical Engineering (ICBME), Teheran, pp. 2527. https:// doi.org/10.1109/ICBME.2015.7404120 [59] Baer W. Conscious Action Theory: an introduction to the event oriented world view, Routledge Press (2020), ISBN: 978-1-138-66746-4 (hbk) (see section 7.7)

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Fig. 1. Conscious interface between the action flow from external real world and internal memory model of reality Fig. 2. Quantitative Parameterization of the Physical Correlates of Consciousness in the comparator function between internal and external action loops Fig. 3. Outline of a balanced tripartite synapse. Neurotransmitters(NT) activate astrocytic

receptors(acR) and postsynaptic receptors(poR) released from the presynapse. The activation of acR by NT increases Ca2+ concentration in the astrocyte and leads to the production of Gliotransmitters(GT). GTs occupy extra-synaptic receptors(esR) and exert a feedback to presynaptic receptors(psR).Gap junctions(GJ) interconnect astrocytes(Ac) forming an glial network. HC:hemichanels Fig. 4. Operation of a Astrocyte Syncytium in classic object terminology Fig. 5. Imbalanced tripartite synapse in depression. Neurotransmitters(NT)

released from the presynapse activate postsynaptic receptors(poR) and astroglial receptors(acR). Upregulation of gap junctions(GJ) up-regulates the expression of acR(1). Overexpressed acR cannot be completely activated by NT causing diminished Ca2+ concentration (down arrow) and production of gliotransmitters(GT) (down arrow). This leads to a protracted activation of poR, extra-synaptic receptors(esR), and a protracted negative feedback on presynaptic receptors(psR) delaying neurotransmission(dashed line) Ca2+ waves propagation in the astroglial network is protracted(down arrow). HC:hemichannels-(modified after [22]). Fig. 6. Imbalanced tripartite synapse in mania. Down-regulation of gap junctions(GJ)(dashed squares) down-regulates (1) the expression of astroglial receptors(acR). Underexpressed acR are flooded (bold lines) by Neurotransmitters(NT) increasing Ca2+ concentration(up arrow)and the production of gliotransmitters(GT) leading to a shortened feedback on presynaptic receptors(psR). Postsynaptic receptors(poR) and extrasynaptic receptors(esR) are also hyperactivated causing a rapid neurotransmission. Rapid Ca2+ wave propagation in the astroglial network. HC:hemichannels ( modified after [34]). Fig. 7. Unbalanced tripartite synapse in schizophrenia. Astroglial

receptors(acR) are nonfunctional(crosses) and cannot be activated by neurotransmitters(NT). Ca2+ and gliotransmitter(GT) production is not activated by NT leading to an unconstrained neurotransmission, since no negative feedback is exerted by NT on presynaptic receptors(psR)(bar). Loss of gap junctions(GJ)(dashed squares) is modified after [43]. Fig. 8. Imbalance between glutamatergic and GABAergic tripartite synapses in epilepsy [57]. a) Glutamate(GLU) hyper-activates postsynaptic receptors(poR) and astroglial receptors(acR).Ca2+ concentration and gliotransmitter(GT) production is excessively increased(double up arrows) leading to a shortened feedback on presynaptic receptors(psR) and hyperactivation of extrasynaptic receptors(esR)excessively depolarizing the postsynapse. Rapid propagation of Ca2+ waves in the astroglial

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network. b) Decreased GABA release (dashed lines) from the presynapse hyperactivates poR and acR. Ca2+ and GT production is diminished(down arrow) causing a protracted feedback on psR and a protracted depolarization of the postsynapse, since extra-synaptic receptors(esR) are hyperactivated by GT (dashed lines). The propagation of Ca2+ waves is protracted(down arrow). The interactions between the gluatamatergic and the GABAergic tripartite synapses are imbalanced HC:hemichannels. ( modified after Mitterauer [22]).

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