A Possible Role of the Glial System in the Pathophysiology
of So-Called Mental Disorders

By Dr. Bernhard J. Mitterauer


1. Introduction

     The so-called mental disorders or psychobiological disorders basically comprise affective psychoses (bipolar disorders or manic-depressive illness) and delusional disorders like schizophrenia. After the description and explanation of the pertinent hypotheses, I will deduce the main symptomatology of the psychiatric disorders from these. Since the theoretical framework proposed is essentially based on glial-neuronal interactions, let me start out with an overview of the glial system in its interaction with the neuronal system.



2. Glial neuronal interaction

2.1. General introduction        

     The nervous tissue of the brain consists of the neuronal system (neurons, axons, dendrites and the glial system (astrocytes, oligodendrocytes with myelin sheaths which enfold the axons and microglia).  Glial cells outnumber neurons in the central nervous system (brain) by a factor of 10 to 1 (Kuffler et.al., 1984).  Virchow (1846) considered them to be merely connective  tissue between the neurons (“nerve glue”).  Meanwhile, experimental results are inspiring a major re-examination of the role of glia in the regulation of neural integration in the central nervous system (Kettenmann and Ransom, 1995; Haydon, 2001).  Glial cells (particularly astrocytes with their processes that contact or even enfold a synapse) modulate the “efficacy of synaptic transmission” (Teichberg, 1991; Mitterauer et. al., 1996; Mitterauer, 2000 b; Oliet et al. 2001).  Signals between astrocytes and neurons can be mediated by glutamate  (Gallo and Ghiani, 2000); acetylcholine (Smit et al., 2001) and other neurotransmitters (Kimelberg, 1998) and by intracellular calcium oscillations in astrocytes which have been hypothesized to affect synaptic cleft calcium concentrations (Cooper, 1995; Newman and Zahs, 1997) and, subsequently, the amount of neurotransmitter released from presynaptic terminals.  In addition to modulating synaptic transmission in neuronal cells, astrocytes may play a direct role in generating pacemaker rhythms (Mitterauer et al, 2000).

     According to my hypothesis, glial cells have a spatio-temporal boundary-setting function in their interaction with the neuronal system in the sense of information structuring. In other words, glial cells (astrocytes, oligodendrocytes) divide the brain into spatially limited areas or compartments, on the one hand, and create functional units in various time scales with the neurons, on the other hand. At least what the neuronal system concerns, there is a general consensus in neuroscience that the brain is compartmentalized (Rall, 1995).

Figure 1. Schematic diagram of two glial-neuronal compartments


    This figure shows a schematic diagram of two glial-neuronal compartments. The entire system is composed of the following cell structures: three receptors (R) are shown that can be occupied by appropriate stimuli (St). Axons (Ax) lead to the corresponding neurons (N). Three processes (Po) lead from an oligodendrocyte (Oc) to axons, where the axons are enveloped by myelin sheaths (Ms). Processes (Pa) lead also from an astrocyte (Ac) via a synapse (Sy) to the neurons. With respect to the neuronal system, the diagram shows three dendrites (D) leading via a synapse to the neurons. Oc and Ac are interconnected via gap junctions (g.j.) and between themselves. As an example, an Ac of compartment x is connected with an Ac of compartment y via a gap junction. So the glial system builds a network per se, called glial syncytium.

    As I already mentioned, it is experimentally well established that glial cells exert an active role in modulating the efficacy of synaptic transmission (Teichberg, 1991; Mitterauer et al, 1996; Oliet et al, 2001; Haydon, 2001; Mitterauer, 2003).


    Now I will mention some experimental indications for the spatial boundary-setting function of the glial system.  Rakic (1988) proposed an experimentally supported “radial unit hypothesis” for the development of the cerebral cortex.


Figure 2. Radial unit model of the development of the cerebral cortex (Rakic, 1988, with permission of the author)

This figure shows the relation between a small patch of the proliferative, ventricular zone (VZ) and its corresponding area within the cortical plate (CP) in the developing cerebrum. Although the cerebral surface in primates expands and shifts during prenatal development, ontogenetic columns (outlined by the cylinders) remain attached to the corresponding proliferative units by the grid of radial glial fibers (RG). Neurons produced between E40 (40th embryonic day) and E100 by a given proliferative unit, migrate in succession along the same radial glial guides (RG) and stack up in reverse order of arrival within the same ontogenetic column. Each migrating neuron (MN) first transverses the intermediate zone (IZ) and then the subplate (SP) which contains interstitial cells and ‘waiting’ afferents from the thalamic radiation (TR) and ipsilateral and contralateral cortico-cortical connections (CC) between E38 and E48. After entering the cortical plate, each neuron bypasses earlier generated neurons and settles at the interface between the CP and the marginal zone (MZ). As a result, proliferative units 1-100 produce ontogenetic columns 1-100, in the same relative position to each other without a lateral mismatch… Thus, the specification of cytoarchitectonic areas and topographic maps depend on the spatial distribution of their ancestors in the proliferative units, whereas the laminar position and phenotype of neurons within ontogenetic columns depends on the time of their origin.

     According to this hypothesis, the ependymal layer of the embryonic cerebral ventricle consists of proliferative units that provide a protomap of prospective cytoarchitectonic areas. The output of the proliferative units is translated via glial guides to the expanding cortex in the form of ontogenetic columns, whose final number for each area can be modified through interaction with afferent input. The radial unit model provides a framework for understanding cerebral evolution, epigenetic regulation of the parcellation of cytoarchitectonic areas. According to Rakic, the cerebral cortex develops from a glial protomap such that an isomorphism exists between the places on the protomap and the cortical columns. One can also say that radial glial cells determine the spatial distribution of neurons in the developing cerebral cortex in the sense of a spatial boundary-setting function. In other words: the radial glia determine the places where the neurons are at work. Hatten (1990) speaks of a glial “scaffold”.

     This spatial boundary-setting function of the glial system is also exhibited in the retina, for example, where Müller cells (radial glia) group neurons into columns. Further, it is established in the olfactory system that the astroglia have a boundary-setting function in the formation of the olfactory glomeruli.

2.2. The concept of tripartite synapses

     Is there also experimental evidence for the glial temporal boundary-setting function?  An impressive example of the glial temporal boundary-setting is represented by the model of tripartite synapses. According to the prevailing view, chemical synaptic transmission exclusively involves bipartite synapses consisting of presynaptic and postsynaptic components and a synaptic cleft, in which a presynaptically released neurotransmitter binds to cognate receptors in the postsynaptic cell. However, there is a new wave of information suggesting that glia, especially astrocytes, are intimately involved in the active control of neuronal activity and synaptic transmission.

     Smit and coworkers (2001) proposed a model of a cholinergic tripartite synapse that might turn out to be a milestone for our understanding of the glial-neuronal interaction. But first let me shortly describe this type of tripartite synapse. These authors identified a glia-derived soluble acetylcholine-binding protein (AChBP), which is a naturally occurring analogue of the ligand-binding domains of the nicotinic acetylcholine receptors (nAChRs). Like the nAChRs, it assembles into a heptamer with ligand-binding characteristics typical of a nicotinic receptor. Presynaptic releases of acetylcholine induce the secretion of AChBP through the glial secretory pathway, and once in the synaptic cleft, it acts as a molecular decoy, binding the transmitter and reducing its availability at the synapse in the sense of a negative feedback on synaptic efficacy.

     This model, which focuses on the role of AChBP in neurotransmission, suggests that there is a basal level of AChBP in the synaptic cleft, maintained by continuous release from the synaptic glial cells. Under conditions of active presynaptic transmitter release, high millimolar concentrations of free ACh will probably activate both postsynaptic receptors and nAChRs on the synaptic glial cells, which would enhance the release of AChBP, thus increasing its concentration in the synaptic cleft. This may either diminish or terminate the ongoing ACh response or raise the concentration of basal AChBP to the extent that subsequent responses to ACh are decreased.

Figure 3. Schematic diagram of a tripartite synapse


      This figure shows a schematic drawing of a tripartite synapse as proposed by Smit and co-workers (2001), but generalized for all neurotransmitters (NT). For the sake of clarity, reference is not made to other modulatory substances such as the functional significance of calcium waves (Charles and Giaume, 2002; Rose et al, 2003). A neurotransmitter is released from the presynaptic terminal ready for occupancy of glial BP and postsynaptic receptors. In parallel, glial receptors are occupied by neurotransmitters, which increase the production and secretion of soluble glial BP into the synapse. The increased levels of soluble BP in the synapse reduces that amount of free neurotransmitter that can bind to postsynaptic receptors, and neurotransmission is inactivated by this form of negative feedback. Once the NT levels have returned to baseline, the BP levels will drop because the glial cells are no longer being stimulated to produce BP; the synapse will return to its initial state, and synaptic information processing can start again. In particular, the role of the glutamatergic tripartite synapse has been documented over the last years (Auld and Robitaille, 2003). The astrocytes which play a role in these synapses do not make use of a BP, but produce glutamate as a transmitter by which they negatively  feedback on the presynaptic element of the synapse. In other words, in tripartite synapses glia have a temporal boundary-setting function in temporarily turning off synaptic information transmission.

     In addition, neuronal synchrony is mediated by astrocytic glutamate through activation of extrasynaptic N-methyl-D-asparate  receptors (Fellin et al, 2004). This is an experimental verification of our “neuro-glial synchronization hypothesis” (Mitterauer et al, 1996) in the sense that glia may actively determine temporal processes in neuronal networks.




Figure 4. Elementary behavioral cycle (Mitterauer, 2000)


     From a cybernetic point of view, this model of a tripartite synapse can be described as an elementary behavioral cycle (Mitterauer 2000a; 2004). Such an interdisciplinary approach could be helpful for interpreting the pathophysiology of both bipolar disorder and schizophrenia. Generally, a living system like man is endowed with intentional programs (hungers, desires, etc.) that strive for realization in the environment (Iberall and McCulloch 1969).



3. Pathophysiological model of so called mental disorders

3.1. Biocybernetic model

     A behavioral cycle represents an intentional relationship of a living system with its environment. Information from the environment actualizes an intentional program. If a living system is able to find appropriate objects for realizing a specific intentional program in its environment, then the cycle is closed and is comparable to an experience based on a negative feedback mechanism that attenuates the initial positive signal, thus down regulating information processing (Fig. 4).



Figure 5. Biocybernetic model of a tripartite synapse (Mitterauer, 2004)


     Such elementary behavioral cycles may also control the information processing in tripartite synapses. The production of a neurotransmitter (NT) in the presynapse can be interpreted as “environmental information” stimulating the expression of glial BP in astrocytes. Glial BP may embody an “intentional program” that is ready for occupancy by an appropriate neurotransmitter. If an appropriate occupancy occurs (“realization of the intentional program”), the glial system negatively feeds back this “experience” to the presynapse. In parallel, this experience is transmitted to other cells in the glial-neuronal networks by occupancy of postsynaptic receptors (“information transmission”). Now, the cycle can start again (Fig. 5).



Figure 6. Balance, imbalance, and unbalance between neurotransmitter (NT) and its

                glial binding protein (gl.BP) (Mitterauer, 2005)


     The interaction between neurotransmitters and glial BP can be system theoretically interpreted (Günther 1963) as balanced, underbalanced, overbalanced, or even unbalanced. Formally speaking, if the variables (BP) dominate the values (NT) available in the system, the system is underbalanced. This may be the case in depression. In contrast, if the values (NT) dominate the variables (BP), the system is overbalanced, which may occur in manic states (Mitterauer 2004). If no appropriate variables (gl.BP) are available, the system is totally unbalanced. Such a synaptic state may be responsible for the pathophysiology of schizophrenia (Fig. 6).


     Now, let me consider in detail the imbalances in tripartite synapses that may cause the so called mental disorders. How could underbalanced tripartite synapses cause depression? Can the main symptoms of depression be explained as a disorder of glial-neuronal interaction in tripartite synapses of the various neurotransmitter types (Fig. 7)?



Figure 7. Underbalanced cholinergic synapse (Mitterauer, 2004)




3.2. Depression

     Supposing that genes responsible for the expression of glial BP are spontaneously or exogenously (stress, etc.) mutated causing overexpression of glial BP, then the overexpression of glial BP will reduce the ACh level in the synapse. This relative lack of ACh will result in an underactivation of both glial nAChRs and postsynaptic receptors as well. The imbalance of the synaptic glial-neuronal interaction may delay the information processing in the sense of protracted “behavioral” cycles. This kind of pathophysiology could be responsible for the psychomotoric retardation of depressive patients, depending on the transmitter systems or brain areas affected.

     As already proposed, glial BP could embody intentional programs that strive for realization by means of neurotransmitter occupancy. Hence, an underbalanced tripartite synapse can be characterized as hyperintentional. Here I see a possible pathophysiological explanation of high aspirations as typical of depressive patients (Bibring 1953). Considering the delayed and imperfect information processing in underbalanced tripartite synapses, feelings of insufficiency may arise on the behavioral level. Furthermore, the synaptic underbalance could be responsible for the disturbance of circadian rhythms, a core symptom of depression. Specifically, disturbances in the synaptic cycle between glial “intentional” programs, presynaptic “environmental” information and the “experience” of appropriate receptor occupancy result in a dysfunction of temporal boundary-setting feedback mechanisms.


     The individual and manifold symptomatology of depression may depend on the types of neurotransmitters or brain regions involved. Since most of the effective treatments of mood disorder were discovered by empiricism, the effectiveness of somatic treatment has propelled neurotransmitter theories rather than vice versa (Post 1995). My approach is contrary to this trend by deducing the pathophysiology of bipolar disorder from a theoretical model. Supposing that a lack of neurotransmitter in the synaptic cleft is responsible for depressive mood, it is conceivable that a treatment with re-uptake inhibitory substances is successful. At first glance, such a therapeutic mechanism should also be effective in tripartite synapses, since an increase of transmitter in the synaptic cleft should balance the excess of glial BP. But what may occur on the glial nAChRs as described in the model of Smit and coworkers? The increased concentration of neurotransmitter in the synaptic cleft may also influence the occupancy of nAChRs causing an additional activation of the overproduction of glial BP, so that the synaptic system remains underbalanced. In line with these considerations a biological treatment of depression should also cope with the overproduction of glial BP, which is probably caused by mutations in pertinent genes. Therefore, antidepressant drugs should not only inhibit transmitter reuptake or block postsynaptic receptors, but they should also be effective on glial nAChRs inhibiting their overactivation. Otherwise, the synaptic glial-neuronal interaction remains unbalanced.


     In this context it should be mentioned that brain diseases like Parkinson’s disease also show a lack of transmitter in pertinent synapses, but this is not necessarily accompanied by a depressive mood. Studies investigating the frequency of depression in Parkinson’s disease have yielded figures ranging between 2.7% and 70% (Burn 2002). Hence, depression may only occur if the glial system is also affected, as I am trying to show.


     Although the monoamine deficiency hypothesis of depression is still the most commonly used model to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that the hypercholinergic neurotransmission associated with depressed mood states may be mediated through excessive neuronal nicotinic receptor activation, and that the therapeutic actions of many antidepressants may in part be mediated via inhibition of these receptors (Shytle and others 2002). According to my interpretation of basic dynamics in tripartite synapses, the cholinergic hypothesis is not contradictory to the prevailing neurotransmitter hypotheses of depression, because the synaptic imbalance may essentially depend on the parameters of glial BP and the presynaptic activation of glial AChRs. In the case of an excess of ACh in the synaptic cleft, the stimulation of glial nAChRs is enhanced leading to an additional overexpression of glial BP, so that the glial-neuronal interaction remains unbalanced despite a cholinergic hyperactivity. Tricyclic antidepressant drugs are very potent substances, but are often rejected due to their cholinergic side effects. Do the therapeutic actions of tricyclic antidepressants concern both the neuronal receptors and the glial receptors in synapses?



3.3. Mania

     Next, which pathophysiological mechanism in tripartite synapses may cause the manic symptomatology in the sense of an extreme mood elevation (Fig. 8)? 



Figure 8. Overbalanced cholinergic tripartite synapse (Mitterauer, 2004)


As already described, a tripartite synapse can be overbalanced due to an underexpression of glial BP. This state may be caused by mutations in genes responsible for the expression of glial BP. As in depression these mutations arise either spontaneously or by exogenous stress.  Unlike the mutations that are hypothesized to cause depression by increasing glial BP expression, these mutations will result in reduced BP expression. Under these conditions, there will be a surplus of neurotransmitter relative to the underexpressed glial BP.  In parallel, glial receptors are flooded with transmitter.  This flooding may also influence the negative feedback mechanism with the effect of shortened cycles of information processing. Since the glial intentional programs embodied by glial BP is immediately realizable and “all is appropriate”, a manic patient is really hypointentional.  Dependent on the transmitter systems or brain areas affected, this synaptic overbalance could cause the pathophysiology of some manic symptoms like euphoria and feelings of omnipotence. Additionally, the rapid synaptic cycles could be explanatory of the manic distractibility, flight of ideas, overactivity and circadian disturbances, especially insomnia.


     The biological treatment of mania focuses on a reduction of the excess of neurotransmitter in the synaptic cleft. This seemingly leads to a normalization of information processing, since the occupancy of glial BP appears to be balanced and glial receptors are not flooded. However, if the underexpression of glial BP continues after a clinical remission of a manic episode, hidden symptoms such as loss of motivation, loss of interests and anhedonia still may persist. This state is often misinterpreted as a depressive reaction to the manic behavior. Hence, a real remission may only occur if the genetically determined imbalance of the glial-neuronal interaction in tripartite synapses is resolved.


3.4. Schizophrenia

     Finally, let me try to explain how unbalanced tripartite synapses could be responsible for the main symptoms of schizophrenia.  Schizophrenia, as a syndrome, is composed of a variety of relatively specific core symptoms. These can be divided into positive and negative symptoms, with the former including hallucinations, delusions, and disorganization, and the latter including anergia, flattening of affect, and poverty of thought content.


      If we suppose that mutations in astrocytes cause the production of non-functional binding proteins in the synaptic cleft, then the synapses affected are unbalanced. They cannot be occupied appropriately by their neurotransmitter ligands in the synaptic cleft.


Figure 9. Unbalanced tripartite synapse (Mitterauer, 2005)


Fig. 9 shows schematically an unbalanced tripartite synapse. Supposing that genes responsible for the expression of glial BP are spontaneously or exogenously (stress, etc.) mutated causing chimeric or non-functional glial BP, then glial BP cannot be occupied by neurotransmitter (NT). Therefore, the postsynaptic receptors are flooded by neurotransmitter. In parallel, neurotransmitter occupy glial receptors (gl.R), activating the production of even more non-functional BP. But that activation has no effect, since the occupancy of gl.BP does not occur! Most importantly no negative feedback of the glial system to the presynapse is possible. So the synaptic information transmission is unconstrained and totally unbalanced. Neuroleptics can reduce this information overflow by occupying postsynaptic receptors, but they are unable to influence the molecular mechanisms responsible for the non-functional gl.BP. If not only gl.BP but also glial receptors are affected, then the glial-neuronal interaction may break down. Dependent on the brain areas affected, this state could cause a severe psychobiological disorder like stuporous catatonia.


Figure 10. Behavioral model of miscreated and unfeasible intentional programs in an

                  unbalanced tripartite synapse (Mitterauer, 2005)


 Interpreted as an elementary behavioral cycle, glial BPs embody an intentional program that “strives” for realization by means of neurotransmitter occupancy. An unbalanced tripartite synapse will exist when non-functional glial BP is unable to bind neurotransmitter and the  intentional program is unfeasible. Since negative feedback is impossible, object related experience does not occur. The behavior of the system is “obsessed” by a flooding of information transmission (Fig. 10). Unbalanced tripartite synapses could be characterized as “dysintentional” because of the unfeasibility of flawed intentional programs. One could also say that schizophrenic patients are suffering from a weakness of volition, as already mentioned by Kraepelin (1919). Frith (1999) also refers to the role of impaired intentions in schizophrenia in the sense of a loss of awareness of intentions underlying typical symptoms. From a purely biological point of view, glia have lost their spatio-temporal boundary setting function in unbalanced tripartite synapses. But what are the consequences of that loss of glial boundary setting for the interaction between the glial syncytium and the neuronal networks in the brain?

     Let us suppose that glial BP or receptors cannot be occupied and that, at least locally, neuronal transmission cannot be interrupted. As a result, neither excitatory nor inhibitory transmitters are able to act in well defined spatio-temporal functional units within the brain. The type of unbalance of transmitter systems will depend on the brain areas and the neuronal circuits affected. A variety of neurotransmitter systems are involved in regulating information flow via the corticostriato-thalamocortical loops, any of which could be altered in schizophrenia (Wyatt and others 1995). Concerning dopamine, a cortico-subcortical imbalance is hypothesized (Davis and others 1991: Abi-Dargham 2003).

     Recent immunohistochemical findings suggest that in the entorhinal and inferior temporal cortex of the schizophrenic brain the expression of the GABA (B) receptor is reduced, raising the possibility that GABA (B) receptor dysfunction is involved in the pathophysiology of schizophrenia (Mizukami and others 2002; Huntsman and others 1998). Extending these considerations further, we are not surprised by the fact that alterations in various transmitter systems have been found in brains of schizophrenic patients, for instance decreased excitatory synapses in the median temporal lobe (Harrison and Eastwood 1998; Schmauss 1996). Therefore, it has been hypothesized that the antipsychotic action of neuroleptic drugs is due to combined neurotransmitter effects and not to a primary abnormality of dopamine neurotransmission alone (Johnstone and others 1999; Meltzer 2003).



Figure 11. Loss of glial boundary-setting function and generalization of neuronal

                  information processing (Mitterauer, 2003)


A loss of the glial boundary-setting function in tripartite synapses is depicted in  Figure 11. The astrocytes (Aci, Acj) of compartment x and compartment y are producing non-functional gl.BPs (asterisks) in the synaptic cleft, so that glia cannot influence neuronal information processing. This genetically determined disturbance results in a “compartmentless” neuronal network displayed as a graph of eight neurons with 28 connecting lines (according to the formula (n2-n)/2). Such a brain is unable to structure the environmental information. One may argue that a glial determination of neuronal networks into functional units is not necessary, since the neuronal system is compartmentalized per se (Rall 1995). However, according to my view, there is a qualitative difference between the purely neuronal compartments and the glia-determined compartments. Neuronal compartments are merely functional for information processing, whereas glial-neuronal compartments may in addition have an information structuring potency that we need for recognizing the qualitative differences between objects and individuals in our environment. That capacity may be lost in a schizophrenic patient. Therefore, one can also speak of a loss of conceptual boundaries.


Table 1. Interpretation of basic schizophrenic symptoms                                      

Loss of boundaries                                                  Symptoms


Conceptual                                                                Thought disorder

Ontological                                                                Delusions

Perceptive                                                                  Hallucinations

Motoric                                                                      Catatonic symptoms

Emotional                                                                  Affective flattening


If the loss of boundaries concerns concepts, a thought disorder results. In the case of a loss of ontological boundaries among the Self and the others (Non-Selves), delusions occur. This loss of ontological boundaries can also affect the perception system in the sense of hallucinations. The loss of boundaries among motor modules shows up in catatonic phenomena. If the boundaries between emotional qualities are lost, affective flattening is the typical symptom.


     Table 1 shows the basic schizophrenic symptoms (American Psychiatric Association 1998), which may be caused by a loss of conceptual boundaries. This disorder can affect cognitive processes like thinking. If a schizophrenic patient is unable to delimit conceptual boundaries among words, thoughts or ideas with different meanings, then meaningless word constructs (neologisms) or disorganized speech are the typical phenomenological manifestations, called “thought disorder”.

     From an ontological point of view, delusions are the consequence of the loss of boundaries between the Self and the others (Non-Selves). Here, the Self is defined as a living system capable of self-observation (Mitterauer and Pritz 1978). One could also say that our brain embodies a distinct ontological locus of self-observation. Everything taking place in the brains of schizophrenic patients is reality, because they cannot differentiate between their inner world and the outer world. Therefore, they cannot see ontological differences between the Self and the Non-Selves. This loss of ontological boundaries may lead to a delusional misinterpretation of reality.

     Hallucinations may be caused by the same disorder. However, the perception systems are phenomenologically affected. A schizophrenic who hears the voice of a person in his head is absolutely convinced that this person is really speaking to him. The loss of ontological boundaries or inner/outer confusion shows its phenomenological manifestation in the auditory system. Such a disorder can also occur in other sensory systems.

     If the loss of boundaries affects the motor system in the brain, the symptomatology is called catatonia. A state of catatonic agitation in which a disinhibited discharge of nearly all motor systems occur, is an expression of motor generalization with raging and screaming as behavioral components. One could also say that the brain’s inability to constrain information processing among motor modules appears in catatonic phenomena. Hence, the catatonic type of schizophrenia represents a serious disorder of motor behavior. Typical symptoms are excessive motor activity and motoric immobility (stupor). Both phenomena appear to be purposeless and not influenced by external stimuli. In such a catatonic state a patient is unable to communicate. He or she cannot see the other. Everything that happens, happens in the brain of the patient.

     Affective flattening is regarded as a negative schizophrenic symptom (Dollfus and Petit 1995). This symptom can also be explained as a loss of boundary setting. The different affective or emotional qualities cannot be produced within the brain and the communication of feelings is disturbed as a result (Holden 2003).

     My hypothesis of the pathophysiology of schizophrenia might be consistent, since the pathological brain mechanism described can explain the main symptoms on the behavioral level. But, in addition we are faced with the question whether this hypothesis could also be explanatory with concern to abnormalities of glial cells recently identified in schizophrenic brains. I think it can.

     Let me give an example. Growing evidence for white matter abnormalities that suggests significant involvement of oligodendroglia in schizophrenia should be integrated in respect to the glial syncytium and the key role of astrocytes within. Findings that several genes encoding myelin-related proteins exhibit consistently reduced expression in schizophrenia may support the neurodevelopment hypothesis. However, what could be the cause that the onset of the clinical symptomatology occurs as late as during adolescence or even adulthood? Supposing that oligodendrocytes do not process axonal information directly, but that they are dependent on the astrocytic information processing via gap junctions in the glial syncytium, then the already outlined dysfunctions of astrocytes may be decisive for the onset of schizophrenic symptomatology.

     According to the stress-diathesis model of the etiology of schizophrenia, environmental stress may activate mutations in astrocytes, since these cells are actively involved in synaptic information processing, whereas oligodendrocytes probably are not. As a consequence, one should interpret the findings of white matter abnormalities in respect to astrocytic dysfunctions.


4. Future prospects

      Some final remarks on future research seem necessary. First of all, the hypotheses proposed here are experimentally testable. What glial binding proteins concerns, up to now they have only been identified in lower animals. In addition, a computer based genome analysis did not find genes that produce these proteins in humans. But I mistrust such analyses, because I think it is very probable that glial binding proteins will eventually be identified in vertebrates, including humans. One of my arguments is this: much of what we know about memory is based on the biochemistry of Aplysia, the California sea slug. Most of the neurotransmitters originally identified in these animals were later shown to be equivalent, with minor exceptions, to those of vertebrates, including man. So why not glial binding proteins?

     If the human brain is really not producing glial binding proteins, then neurotransmitters produced in astrocytes can also achieve a negative feedback mechanism in tripartite synapses, which already has been experimentally identified. However, the glial binding protein hypotheses have a greater explanatory power.

     Last but not least, let me shortly comment on the conception of intentionality or intentional programs, basic for every explanatory model of human behavior. Recently, I have elaborated a formal, biomimetic model concerning where and how intentional programs could be generated in our brain. It can be formally shown that the glial syncytium may be a promising candidate system, especially with respect to the multifunctionality of gap junctions. However, this topic would require a separate study.

     Considering the structural and functional complexity of the generation of intentional programs in our brain, I am afraid that experimental brain research is reaching technical limits. Therefore, I see a real alternative in robotics. If a biomimetic and formally described brain model is technically implemented in a robot brain, then the behavior of such a mobile intentional agent teaches us where we are right and where we are wrong. However, I am convinced that the agent can only show a human-like behavior if the engineer is able to implement the glial-neuronal double structure and its glial determined interactions.



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