Pathophysiology of Schizophrenia Based on Impaired Glial-Neuronal Interactions

DOI: 10.4236/ojmp.2014.32016   PDF   HTML   XML   4,690 Downloads   6,954 Views   Citations


The model of impaired glial-neuronal interactions in schizophrenia is based on the core hypothesis that non-functional astrocyte receptors may cause an unconstrained synaptic information flux such that glia lose their modulatory function in tripartite synapses. This may lead to a generalization of information processing in the neuronal networks responsible for delusions and hallucinations on the behavioral level. In this acute paranoid stage of schizophrenia, non-functional astrocytic receptors or their loss decompose the astrocyte domain organization with the effect that a gap between the neuronal and the glial networks arises. If the illness progresses the permanent synaptic neurotransmitter flux may additionally impair the oligodendrocyte-axonic interactions, accompanied by a “creeping” decay of oligodendroglia, axons and glial gap junctions responsible for severe cognitive impairment. Here we may deal with after-effects caused by the basic fault of information processing in tripartite synapses. The gaps between the neuronal and glial networks prohibit the neuronal reality testing of intentional programs presumably generated in the glial networks, called schizophrenic dysintentionality. In non-schizophrenic delusions glia may not be disturbed, but exhausted extrasynaptic information processing may cause an unconstrained synaptic flux responsible for delusions.

Share and Cite:

B. Mitterauer, "Pathophysiology of Schizophrenia Based on Impaired Glial-Neuronal Interactions," Open Journal of Medical Psychology, Vol. 3 No. 2, 2014, pp. 126-140. doi: 10.4236/ojmp.2014.32016.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] V. Parpura, M. T. Heneka, V. Montana, S. H. Oliet, et al., “Glial Cells in (Patho)physiology,” Journal of Neuro-chemistry, Vol. 121, No. 1, 2012, pp. 4-27.
[2] H. Meltzer, “Multiple Neurotransmitters Involved in Antipsychotic Drug Action,” In: S. Kapur and Y. Lecrubier, Eds., Dopamine in the Pathophysiology and Treatment of Schizophrenia, Martin Dunitz, London, 2003, pp. 177-205.
[3] S. Berge and T. Koenig, “Cerebral Disconnectivity: An Early Event in Schizophrenia,” Neuroscientist, Vol. 14, No. 1, 2008, pp. 19-45.
[4] K. J. Friston, “The Disconnection Hypothesis,” Schizophrenia Research, Vol. 30, No. 2, 1998, pp. 115-125.
[5] P. Erdi, B. Flaugher, T. Jones, B. Ujfalussy, L. Zalanyi and V. A. Diwadkar, “Computational Approach to Schizophrenia. Disconnection Syndrome and Dynamical-pharmacology,” AIP Conference Proceedings, Varenna, 24-28 September 2007, pp. 65-87.
[6] K. I. Vadakkan, “A Structure-Function Mechanism for Schizophrenia,” Frontiers in Psychiatry, Vol. 3, No. 108, 2012.
[7] H. G. Bernstein, J. Steiner and B. Bogerts, “Glial Cells in Schizophrenia: Pathophysiological Significance and Possible Consequences for Therapy,” Expert Review Neuro-therapy, Vol. 9, No. 7, 2009, pp. 1059-1071.
[8] X. Di, R. C. Chan and Q. Gong, “White Matter Reduction in Patients with Schizophrenia as Revealed by Voxel-Based Morphometry: An Activation Likely Hood Estimation Meta-Analysis,” Progress in Neuropsychopharmacology, Biology and Psychiatry, Vol. 33, No. 8, 2009, pp. 1390-1394.
[9] M. Kyriakopoulos, R. Perez-Iglesias, J. B. Woolley, R. A. Kamaan, N. S. Vyas, G. J. Barker, S. Frangou and P. K. McGuire, “Effect of Age at Onset of Schizophrenia on White Matter Abnormalities,” British Journal of Psychiatry, Vol. 195, No. 4, 2009, pp. 346-353.
[10] A.E. Steffek, “The Role of Astrocytes in the Pathophysiology of Schizophrenia,” Dissertation, University of Michigan, Ann Arbor, 2007, 159 p.
[11] B. Mitterauer, “An Interdisciplinary Approach towards a Theory of Consciousness,” Biosystems, Vol. 45, No. 2, 1998, pp. 99-121.
[12] B. Mitterauer, “Where and How Could Intentional Programs Be Generated in the Brain? A Hypothetical Model Based on Glial-Neuronal Interactions,” Biosystems, Vol. 88, No. 1-2, 2007, pp. 101-112.
[13] H. Kettenmann and B. R. Ransom, “Neuroglia,” Oxford University Press, Oxford, 2005.
[14] M. M. Halassa, T. Fellin and P. G. Haydon, “Tripartite Synapses: Roles for Astrocytic Purins in the Control of Synaptic Physiology and Behavior,” Neuropharmacology, Vol. 57, No. 4, 2009, pp. 343-346.
[15] D. A. Rusakov, “Depletion of Extracellular Ca2+ Prompts Astroglia to Modulate Synaptic Network Activity,” Science Signalling, Vol. 5, No. 208, 2012, p. 4.
[16] R. Dermietzel and D. C. Spray, “From Neuro-Glue to Glia: A Prologue,” Glia, Vol. 24, No. 1, 1998, pp. 1-7.<1::AID-GLIA1>3.0.CO;2-A
[17] A. Araque, V. Parpura, R. P. Sanzgiri and P. G. Haydon, “Tripartite Synapses: Glia, the Unacknowledged Partner,” Trends in Neuroscience, Vol. 22, No. 5, 1999, pp. 208-215.
[18] B. R. Ransom and Z. Ye, “Gap Junctions and Hemichannels,” In: H. Kettenmann and B. R. Ransom, Eds., Neuroglia, Oxford University Press, Oxford, 2005, pp. 177-189.
[19] E. A. Newman, “Glia and Synaptic Transmission,” In: H. Kettenmann and B. R. Ransom, Eds., Neuroglia, Oxford University Press, Oxford, 2005, pp. 355-366.
[20] D. Stellwagen and R. C. Malenka, “Synaptic Scaling Mediated by Glial TNF-Alpha,” Nature, Vol. 440, No. 7087, 2006, pp. 1054-1059.
[21] D. S. Auld and R. Robitaille, “Glial Cells AND Neuro-transmission: An Inclusive View of Synaptic Function,” Neuron, Vol. 40, No. 2, 2003, pp. 389-400.
[22] N. A. Oberheim, X. Wang, S. Goldman and M. Nedergaard, “Astrocytic Complexity Distinguishes the Human Brain,” Trends in Neuroscience, Vol. 29, No. 10, 2006, pp. 547-553.
[23] A. Pereira and F. A. Furlan, “Astrocytes and Human Cognition: Modeling Information Integration and Modulation of Neuronal Activity,” Progress in Neurobiology, Vol. 92, No. 3, 2010, pp. 405-420.
[24] H. Kettenmann and C. Steinhauser, “Receptors for Neurotransmitters and Hormones,” In: H. Kettenmann and B. R. Ransom, Eds., Neuroglia, Oxford University Press, Oxford, 2005, pp. 131-145.
[25] M. Santello and A. Volterra, “Astrocytes as Aide-Mémoires,” Nature, Vol. 463, No. 7278, 2010, pp. 169-170.
[26] B. Mitterauer, “Significance of the Astrocyte Domain Organization for Qualitative Information Structuring in the Brain,” Advances in Bioscience and Biotechnology, Vol. 1, 2010, pp. 391-397.
[27] R. D. Fields, A. Araque, H. Johansen-Berg, S. Lien, et al., “Glial Biology in Learning and Cognition,” Neuroscientist, 2013.
[28] R. Káradóttir and D. Attwell, “Neurotransmitter Receptors in the Life and Death of Oligodendrocytes,” Neuroscience, Vol. 145, No. 4, 2007, pp. 1426-1438.
[29] B. Mitterauer and B. Kofler-Westergren, “Possible Effects of Synaptic Imbalances on Oligodendrocyte-Axonic Interactions in Schizophrenia: A Hypothetical Model,” Frontiers in Psychiatry, Vol. 2, 2011, p. 15.
[30] R. D. Fields, “Change in the Brain’s White Matter,” Science, Vol. 330, No. 6005, 2010, pp. 768-769.
[31] B. Stevens, S. Tanner and R. D. Fields, “Control of Myelination by Specific Patterns of Neural Impulses,” Journal of Neuroscience, Vol. 18, No. 22, 1998, pp. 9303-9311.
[32] T. Ishibashi, K. A. Dakin, B. Stevens, P. R. Lee, S. V. Kozlov, C. L. Stewart and R. D. Fields, “Astrocytes Promote Myelination in Response Toelectrical Impulses,” Neuron, Vol. 49, No. 6, 2006, pp. 823-832.
[33] B. Stevens, S. Porta, L. L. Haak, V. Gallo and R. D. Fields, “Adenosine, a Neuron-Glial Transmitter Promoting Myelination in the CNS in Response to Action Potentials,” Neuron, Vol. 36, No. 5, 2002, pp. 855-868.
[34] R. D. Fields and Y. Ni, “Nonsynaptic Communication through ATP Release from Volume-Activated Anion Channels in Axons,” Science Signalling, Vol. 3, No. 142, 2010, p. ra73.
[35] F. F. De-Miguel and K. Fuxe, “Extrasynaptic Neurotransmission as a Way of Modulating Neuronal Functions,” Frontiers in Physiology, Vol. 3, 2012, p. 16.
[36] A. Torres, F. Wang, Q. Xu, T. Fujita, R. Dobrowolski, K. Willecke, T. Takano and M. Nedergaard, “Extracellular Ca2+ Acts as a Mediator of Communication from Neurons to Glia,” Science Signaling, Vol. 5, No. 208, 2012, p. ra8.
[37] G. Werner and B. J. Mitterauer, “Neuromodulatory Systems,” Frontiers in Neural Circuits, Vol. 7, 2013, p. 36.
[38] W. T. Carpenter and R. W. Buchanan, “Schizophrenia: Introduction and Overview,” In: H. J. Kaplan and B. J. Sadock, Eds., Comprehensive Textbook of Psychiatry, Williams and Wilkins, Baltimore, 1995, pp. 899-902.
[39] B. S. Shastry, “Schizophrenia: A Genetic Perspective,” International Journal of Molecular Medicine, Vol. 9, No. 3, 2002, pp. 207-212.
[40] S. Kapur and Y. Lecrubier, “Dopamine in the Pathophysiology and Treatment of Schizophrenia,” Martin Dunitz, London, 2003.
[41] M. F. Lenzenweger, G. McLachlan and D. B. Rubin, “Resolving the Latentstructure of Schizophrenia Endophenotypes Using Expectation-Maximizationbased Finitemixture Modeling,” Journal of Abnormal Psychology, Vol. 116, No. 1, 2007, pp. 16-29.
[42] S. Fisher and S. E. Cleveland, “Body Image and Personality,” Dover, New York, 1968.
[43] A. Sims, “An Overview of the Psychopathology of Percaption: First Rank Symptoms as a Localizing Sign in Schizophrenia,” Psychopathology, Vol. 24, No. 6, 1991, pp. 369-374.
[44] B. Mitterauer, “The Loss of Self-Boundaries: Towards a Neuromolecular Theory of Schizophrenia,” Biosystems, Vol. 72, No. 3, 2003, pp. 209-215.
[45] American Psychiatric Association, “Diagnostic and Statistical Manual of Mental Disorders,” American Psychiatric Association, Washington, 1998.
[46] B. Mitterauer and W. F. Pritz, “The Concept of the Self: A Theory of Self-Observation,” International Review in Psychoanalysis, Vol. 5, 1978, pp. 179-188.
[47] R. Arajarvi, T. Varilo, J. Haukka, J. Suvissari, J. Suokas, H. Juvonen, M. Muhonen, J. Lonnquist, et al., “Affective Flattening and Alogia Associate with Familial Form of Schizophrenia,” Psychiatry Research, Vol. 141, No. 2, 2006, pp. 161-172.
[48] C. Holden, “Behavioral Genetics. Getting the Short End of the Allele,” Science, Vol. 301, No. 5631, 2003, pp. 291-293.
[49] K. Hashimoto, G. Engberg, E. Shimizu, C. Nordin, L. H. Lindstrom and M. Iyo, “Elevated Glutamine/Glutamate Ratio in Cerebrospinal Fluid of First Episode and Drug Naive Schizophrenic Patients,” BMC Psychiatry, Vol. 5, 2005, p. 6.
[50] V. Faa, A. Cobana, F. Incani, L. Constantino, A. Cao and M. C. Rosatelli, “A Synchronous Mutation in the CFTR Gene Causes Aberrant Splicing in an Italian Patient Affected by a Mild Form of Cystic Fibrosis,” Journal of Molecular Diagnostics, Vol. 12, No. 3, 2010, pp. 380-383.
[51] G. Wang and T. A. Cooper, “Splicing in Disease: Disruption of the Splicing Code and the Decoding Machinery,” Nature Reviews Genetics, Vol. 8, No. 10, 2007, pp. 749-761.
[52] L. Quintana-Murci, “Gene Losses in the Human Genome,” Science, Vol. 335, No. 6070, 2012, pp. 806-807.
[53] A. Poduri, G. Evrony, X. Cai and C. A. Walsh, “Somatic Mutation, Genomic Variation, and Neurological Disease,” Science, Vol. 341, No. 6141, 2013, Article ID: 1237758.
[54] Z. Deng, J. L. Sobell and J. A. Knowles, “Epigenetic Alterations in Schizophrenia,” Focus, Vol. 8, No. 3, 2010, pp. 358-365.
[55] B. A. Saakov, T. A. Khoruzhaya and E. A. Bardakhchyan, “Ultrastructural Mechanisms of Serotonin Demyelination,” Bulleten Eksperimental noi Biologii I Meditsiny, Vol. 83, No. 5, 1977, pp. 606-610.
[56] E. Alberdi, M. V. Sanchez-Gomez, I. Torre, M. Domercq, A. Perez-Samatin, F. Pérez-Cerdá and C. Matute, “Activation of Kainate Receptors Sensitizes Oligodendrocytes to Complement Attack,” Journal of Neuroscience, Vol. 26, No. 12, 2006, pp. 3220-3228.
[57] L. R. Skelly, V. Calhoun, S. A. Meda, J. Kim, D. H. Mathalon and G. D. Pearlson, “Diffusion tensor Imaging in Schizophrenia: Relationship to Symptoms,” Schizophrenia Research, Vol. 98, No. 1, 2008, pp. 157-162.
[58] N. Takahashi, T. Sakurai, K. L. Davis and J. D. Buxbaum, “Linking Oligodendrocyte and Myelin Dysfunction to Neurocircuitry Abnormalities in Schizophrenia,” Progress in Neurobiology, Vol. 93, No. 1, 2010, pp. 13-24.
[59] M. N. Hostad, D. Segal, N. Takahashi, T. Sakurai, J. D. Buxbaum and P. R. Hof, “Linking White and Grey Matter in Schizophrenia: Oligodendrocyte and Neuron Pathology in the Prefrontal Cortex,” Frontiers in Neuroanatomy, Vol. 3, 2009, p. 9.
[60] R. D. Fields, “The Other Brain,” Simon and Schuster, New York, 2009.
[61] J. M. Robertson, “The Astrocentric Hypothesis: Proposed Role of Astrocytes in Consciousness and Memory Formation,” Journal of Physiology, Vol. 96, No. 3-4, 2002, pp. 251-255.
[62] B. Mitterauer, “Loss of Function of Glial Gap Junctions May Cause Severe Cognitive Impairments in Schizophrenia,” Medical Hypotheses, Vol. 73, No. 3, 2009, pp. 393-397.
[63] R. C. Wolf, A. Hose, K. Frasch, H. Walter and N. Vasic, “Volumetric Abnormalities associated with Cognitive Deficits in Patients with Schizophrenia,” European Psychiatry, Vol. 23, No. 8, 2008, pp. 541-548.
[64] C. D. Frith, “The Cognitive Neuropsychology of Schizophrenia,” Psychology Press, East Sussex, 1992.
[65] B. J. Mitterauer, “Qualitative Information Processing in Tripartite Synapses: A Hypothetical Model,” Cognitive Computation, Vol. 4, No. 2, 2011, pp. 181-194.
[66] B. Mitterauer, “Nonfunctional Glial Proteins in Tripartite Synapses: A Pathophysiological Model of Schizophrenia,” Neuroscientist, Vol. 11, No. 3, 2005, pp. 192-198.
[67] N. Markis, L. J. Seidman, T. Ahern, D. N. Kennedy, V. S. Caviness, M. T. Tsuang and J. M. Goldstein, “White Matter Volume Abnormalities and Association with Symptomatology in Schizophrenia,” Psychiatry Research, Vol. 183, No. 1, 2010, pp. 21-29.
[68] M. V. Sofroniew, “Reactive Astrocytes in Neural Repair and Protection,” Neuroscientist, Vol. 11, No. 5, 2005, pp. 400-407.
[69] A. S. Brown, “The Risk for Schizophrenia from Childhood and Adulthood Infections,” American Journal of Psychiatry, Vol. 165, No. 1, 2008, pp. 7-10.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.