Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways
Chao Deng1,2,3* 
Brian Dean4,5*- 1Antipsychotic Research Laboratory, Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
- 2Centre for Translational Neuroscience, School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- 3Schizophrenia Research Institute, Sydney, NSW, Australia
- 4Molecular Psychiatry Laboratory, Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- 5Department of Psychiatry, The University of Melbourne, Parkville, VIC, Australia
Schizophrenia is a complex disorder involving dysregulation of multiple pathways in its pathophysiology with strong evidence to support roles for dopaminergic, glutamatergic, GABAergic, and cholinergic neurotransmitter systems and their interactions in the pathophysiology of the disorder (Benes, 2009; Karam et al., 2010; Gibbons et al., 2013). Additionally, evidence from genetic, post-mortem and animal studies over the past decade has identified a number of susceptibility factors for schizophrenia, including neuregulin 1 (Nrg1) and its receptor ErbB4, disrupted-in-schizophrenia-1 (DISK1), catechol-O-methyl transferase (COMT), BDNF, and Akt, along with their related pathways, that interact closely with dopaminergic, glutamatergic, and GABAergic neurotransmitter systems (Karam et al., 2010). Hence a key question is how these neurotransmitter systems and their interactions contribute to the pathophysiology of schizophrenia and whether interactive changes in these pathways occur in early brain development, based on the view of schizophrenia as a developmental disorder?
This Frontier Research Topic has brought together leading experts in the field to address these questions from different angles in nine reviews, one theoretic article and two research articles. The first four articles focus on the roles and interactions of neurotransmitters in the pathophysiology of psychiatric disorders. Snyder and Gao (2013) provide an excellent review of NMDA receptor hypofunction hypothesis, suggesting NMDA receptor hypofunction as a convergence point for progression and symptoms of schizophrenia. They also discuss evidence on altered NMDA receptor subunits in schizophrenia and how these alterations interact with multiple schizophrenia susceptibility genes that lead to NMDA receptor dysfunction during development (Snyder and Gao, 2013). Scarr et al. (2013) present an in depth and very detailed coverage of cholinergic involvement in schizophrenia and how it interacts with other neurotransmitters including glutamate, dopamine, GABA and serotonin, as well as its links with the inflammatory/immune system. The review also provides a frame work for testable hypotheses of the potential outcomes of a dysregulated cholinergic system for research into the pathophysiologies of psychiatric disorders (Scarr et al., 2013). Cognitive deficits are considered core symptoms of schizophrenia, while abnormalities in gamma oscillations have been identified in schizophrenia patients that are associated with deficits in attention, working memory, and other cognitive functions (Uhlhaas and Singer, 2010). Furth et al. (2013) reviewed the central role of dopamine D4 receptor in the generation of gamma frequency synchronization of neural networks and cognitive processes via their influence on parvalbumin-expressing GABAergic interneurons. They also examined their close synergistic relationship with neuregulin/ErbB4 signaling, in particular in the prefrontal cortex and hippocampus two major brain regions implicated in schizophrenia (Furth et al., 2013). Furthermore, there has been increasing evidence linking oxidative stress to the pathophysiology of schizophrenia. In their article, Yao and his team reviewed some of these findings, focusing particularly on their findings on homeostatic imbalance of purine catabolism and its association with monoamine neurotransmitters in first episode antipsychotic-naïve patients with schizophrenia (Yao et al., 2013).
In the following three papers, Chana et al. have provided an excellent review of the current progress in the search for biomarkers for schizophrenia and psychosis, focusing on biomarkers for major neurotransmitter systems in post-mortem brain studies, as well as covering some recent and exciting studies in microRNA dysregulation in both the blood and brain of schizophrenia patients (Chana et al., 2013). It is followed by a very timely review of current knowledge on the features of polysialic acid and their synthesizing enzymes (specially ST8SIA2), their functions in regulations of cell adhesion, ion channels, neurotrophins (such as BDNF) and catecholamine neurotransmitters (particularly dopamine), in light of several recent lines of evidence linking polysialic acid to schizophrenia (Sato and Kitajima, 2013). Iwakura and Nawa provide a very clear overview of the ErbB1-4 dependent EGF/neuregulin signals, their role in regulating the development and function of the central nervous system, and the contribution of deficits in ErbB signaling to schizophrenia and neurological disease (Iwakura and Nawa, 2013).
Four articles discuss the animal model of schizophrenia, two of which address the Nrg1-cannabinoid interaction in a hypomorphic Nrg1 (Nrg1 HET) mouse model of schizophrenia. In an original study, Spencer et al. investigated Nrg1-cannabinoid interaction in the hippocampus using proteomics, in which they identified alterations of some proteins involved in vesicular release of neurotransmitters, serotonergic neurotransmission, and growth factor release in response to Nrg1 hypomorphism and Nrg1-cannabinoid interaction (Spencer et al., 2013). In a short review, Karl and Arnold further discussed the complex neuro-behavioral effects of Nrg1-cannabinoid interaction and its clinical implications (Karl and Arnold, 2013). In a BDNF heterozygous mouse model, Manning and van den Buuse investigated the effects of chronic methamphetamine treatment during late adolescence/early adulthood on a behavioral endophenotype related to the positive symptoms of schizophrenia, prepulse inhibition (PPI) of the acoustic startle reflex (Manning and van den Buuse, 2013). In the fourth animal model paper, altered dopamine ontogeny in the developmentally vitamin D deficient rat model and its relevance to schizophrenia were reviewed (Kesby et al., 2013). This review suggests that early alterations in dopamine ontogeny are a core feature in the pathophysiology of schizophrenia representing a critical aspect useful to a model of this disease.
Finally, in the context of schizophrenia as a neurodevelopmental disorder, Catts et al. (2013) discuss elegantly the normal development of the prefrontal cortex on the molecular and cellular levels in line with cognitive development, as well as the timing of cognitive decline in schizophrenia. They proposed to reconsider schizophrenia as an outcome from a failure to reach the final state of cortical maturation resulting in retainment of an immature cortex rather than resulting from an excess of adolescent synaptic pruning (Catts et al., 2013).
In summary, these studies illustrate clearly the interactive nature of specific pathways on different levels of the brain from molecular and cellular pathways, and neural circuits to functional deficits contributing to the pathophysiology of schizophrenia. We believe that this Frontier Research Topic will stimulate the development of future collaborative and interdisciplinary research to reveal the unknown mechanisms underlying the pathophysiology of schizophrenia.
References
Benes, F. M. (2009). Neural circuitry models of schizophrenia: is it dopamine, GABA, glutamate, or something else. Biol. Psychiatry 65, 1003–1005. doi: 10.1016/j.biopsych.2009.04.006
Catts, V. S., Fung, S. J., Long, L. E., Joshi, D., Vercammen, A., Allen, K. M., et al. (2013). Rethinking schizophrenia in the context of normal neurodevelopment. Front. Cell. Neurosci. 7:60. doi: 10.3389/fncel.2013.00060
Chana, G., Bousman, C. A., Money, T. T., Gibbons, A., Gillett, P., Dean, B., et al. (2013). Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis. Front. Cell. Neurosci. 7:95. doi: 10.3389/fncel.2013.00095
Furth, K. E., Mastwal, S., Wang, K. H., Buonanno, A., and Vullhorst, D. (2013). Dopamine, cognitive function, and gamma oscillations: role of D4 receptors. Front. Cell. Neurosci. 7:102. doi: 10.3389/fncel.2013.00102
Gibbons, A. S., Scarr, E., Boer, S., Money, T., Jeon, W.-J., Felder, C., et al. (2013). Widespread decreases in cortical muscarinic receptors in a subset of people with schizophrenia. Int. J. Neuropsychopharmacol. 16, 37–46. doi: 10.1017/S1461145712000028
Iwakura, Y., and Nawa, H. (2013). ErbB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and Parkinson's disease. Front. Cell. Neurosci. 7:4. doi: 10.3389/fncel.2013.00004
Karam, C. S., Ballon, J. S., Bivens, N. M., Freyberg, Z., Girgis, R. R., Lizardi-Ortiz, J. E., et al. (2010). Signaling pathways in schizophrenia: emerging targets and therapeutic strategies. Trends Pharmacol. Sci. 31, 381–390. doi: 10.1016/j.tips.2010.05.004
Karl, T., and Arnold, J. C. (2013). What does a mouse tell us about neuregulin 1—cannabis interactions. Front. Cell. Neurosci. 7:18. doi: 10.3389/fncel.2013.00018
Kesby, J. P., Cui, X., Burne, T. H. J., and Eyles, D. W. (2013). Altered dopamine ontogeny in the developmentally vitamin D deficient rat and its relevance to schizophrenia. Front. Cell. Neurosci. 7:111. doi: 10.3389/fncel.2013.00111
Manning, E. E., and van den Buuse, M. (2013). BDNF deficiency and young-adult methamphetamine induce sex-specific effects on prepulse inhibition regulation. Front. Cell. Neurosci. 7:92. doi: 10.3389/fncel.2013.00092
Sato, C., and Kitajima, K. (2013). Impact of structural aberrancy of polysialic acid and its synthetic enzyme ST8SIA2 in schizophrenia. Front. Cell. Neurosci. 7:61. doi: 10.3389/fncel.2013.00061
Scarr, E., Gibbons, A. S., Neo, J., Udawela, M., and Dean, B. (2013). Cholinergic connectivity: it's implications for psychiatric disorders. Front. Cell. Neurosci. 7:55. doi: 10.3389/fncel.2013.00055
Snyder, M. A., and Gao, W.-J. (2013). NMDA hypofunction as a convergence point for progression and symptoms of schizophrenia. Front. Cell. Neurosci. 7:31. doi: 10.3389/fncel.2013.00031
Spencer, J. R., Darbyshire, K. M. E., Boucher, A. A., Kashem, M. A., Long, L. E., McGregor, I. S., et al. (2013). Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: a hippocampal proteomic study in mice. Front. Cell. Neurosci. 7:15. doi: 10.3389/fncel.2013.00015
Uhlhaas, P. J., and Singer, W. (2010). Abnormal neural oscillations and synchrony in schizophrenia. Nat. Rev. Neurosci. 11, 100–113. doi: 10.1038/nrn2774
Keywords: schizophrenia, dopamine, GABA, acetylcholine, neurodevelopment, glutamate, neuregulin 1, ErbB4
Citation: Deng C and Dean B (2013) Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways. Front. Cell. Neurosci. 7:238. doi: 10.3389/fncel.2013.00238
Received: 02 November 2013; Accepted: 13 November 2013;
Published online: 28 November 2013.
Edited by:
Egidio D'Angelo, University of Pavia, ItalyCopyright © 2013 Deng and Dean. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: chao@uow.edu.au; anddali@unimelb.edu.au