Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways

Abstract

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 . 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...

Editorial: Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways, volume II

“…Editorial: Mapping the pathophysiology of schizophrenia: interactions between multiple cellular pathways, volume II A decade ago, the first edition of "Mapping the Pathophysiology of Schizophrenia: Interactions Between Multiple Cellular Pathways" was curated by Deng and Dean (2013a). This Research Topic was highly successful, with contributing articles accessed over 260,000 times, and the Topic also published as a book (Deng and Dean, 2013b). The breadth of the topics in Volume I was (and remains) reflective of the complexity of schizophrenia and the challenges in fully elucidating its pathophysiology.…”