Pathophysiology of Schizophrenia

Falkai, Peter; Schmitt, Aurore; Cannon, Tyrone D.

doi:10.1002/9780470978672.ch2

Cited by 14 publications

(10 citation statements)

References 237 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Microbial metabolic pathways found in schizophrenia samples have also been described in samples from the respiratory and digestive tracts such as in gingiva, oral cavity, and stool (M00239, M00276, M00200, M0028, M0029), reinforcing the notion that oral and gut microbial communities share features and are associated ( Meehan & Beiko, 2012 ; Sczesnak et al, 2011 ; Seekatz et al, 2014 ; Segata et al, 2012 ). Dominant hypotheses for the pathophysiology of schizophrenia, as well as recent genetic studies, point to neurotransmitter disturbances in glutamatergic and dopaminergic activities ( Falkai, Schmitt & Cannon, 2011 ; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014 ). While we found glutamate related pathways to be more abundant in schizophrenia samples, the design and scope of this study does not allow us to evaluate mechanistic hypotheses regarding pathophysiology of schizophrenia and the potential contribution of the microbiome.…”

Section: Discussionmentioning

confidence: 99%

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls

Castro-Nallar

Bendall

Pérez‐Losada

et al. 2015

PeerJ

226

147

View full text Add to dashboard Cite

The role of the human microbiome in schizophrenia remains largely unexplored. The microbiome has been shown to alter brain development and modulate behavior and cognition in animals through gut-brain connections, and research in humans suggests that it may be a modulating factor in many disorders. This study reports findings from a shotgun metagenomic analysis of the oropharyngeal microbiome in 16 individuals with schizophrenia and 16 controls. High-level differences were evident at both the phylum and genus levels, with Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria dominating both schizophrenia patients and controls, and Ascomycota being more abundant in schizophrenia patients than controls. Controls were richer in species but less even in their distributions, i.e., dominated by fewer species, as opposed to schizophrenia patients. Lactic acid bacteria were relatively more abundant in schizophrenia, including species of Lactobacilli and Bifidobacterium, which have been shown to modulate chronic inflammation. We also found Eubacterium halii, a lactate-utilizing species. Functionally, the microbiome of schizophrenia patients was characterized by an increased number of metabolic pathways related to metabolite transport systems including siderophores, glutamate, and vitamin B12. In contrast, carbohydrate and lipid pathways and energy metabolism were abundant in controls. These findings suggest that the oropharyngeal microbiome in individuals with schizophrenia is significantly different compared to controls, and that particular microbial species and metabolic pathways differentiate both groups. Confirmation of these findings in larger and more diverse samples, e.g., gut microbiome, will contribute to elucidating potential links between schizophrenia and the human microbiota.

show abstract

Section: Discussionmentioning

confidence: 99%

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls

Castro-Nallar

Bendall

Pérez‐Losada

et al. 2015

PeerJ

226

147

View full text Add to dashboard Cite

show abstract

“…More specifically, mRNA and protein levels of parvalbumin-positive interneurons were shown to be affected in SZ, while cell number and density were not consistently reduced [55]. However, a dysfunction of inhibitory interneurons may contribute to a hypofunction of the NMDA receptor and a glutamatergic imbalance, leading to cognitive deficits and negative and positive symptoms [52]. Recently, it has become evident that, besides the well-known myelination of glutamatergic projection neurons, a large fraction of myelin ensheathes axons of cortical inhibitory neurons, especially of parvalbumin-positive basket cells [56].…”

Section: The Intercellular Interactions Of Oligodendrocytes With Micrmentioning

confidence: 98%

“…Oligodendrocytes have glutamatergic n-methyl-D-aspartate (NMDA) receptors, and our group showed that NMDA receptor hypofunction after MK-801 treatment of human cell cultures causes oligodendrocyte dysfunction by inducing deficits in glycolysis [51]. MK-801 is a potent NMDA receptor antagonist, and treatment with this class of antagonists represents the most reliable pharmacological model of the cognitive, positive, and negative symptoms of SZ [52,53]. Therefore, NMDAR antibodies, as part of an inflammatory process, may influence oligodendrocyte pathology.…”

Section: The Intercellular Interactions Of Oligodendrocytes With Micrmentioning

confidence: 99%

Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

Raabe

Slapakova

Rossner

et al. 2019

Cells

Self Cite

View full text Add to dashboard Cite

Imaging and postmortem studies have revealed disturbed oligodendroglia-related processes in patients with schizophrenia and provided much evidence for disturbed myelination, irregular gene expression, and altered numbers of oligodendrocytes in the brains of schizophrenia patients. Oligodendrocyte deficits in schizophrenia might be a result of failed maturation and disturbed regeneration and may underlie the cognitive deficits of the disease, which are strongly associated with impaired long-term outcome. Cognition depends on the coordinated activity of neurons and interneurons and intact connectivity. Oligodendrocyte precursors form a synaptic network with parvalbuminergic interneurons, and disturbed crosstalk between these cells may be a cellular basis of pathology in schizophrenia. However, very little is known about the exact axon-glial cellular and molecular processes that may be disturbed in schizophrenia. Until now, investigations were restricted to peripheral tissues, such as blood, correlative imaging studies, genetics, and molecular and histological analyses of postmortem brain samples. The advent of human-induced pluripotent stem cells (hiPSCs) will enable functional analysis in patient-derived living cells and holds great potential for understanding the molecular mechanisms of disturbed oligodendroglial function in schizophrenia. Targeting such mechanisms may contribute to new treatment strategies for previously treatment-resistant cognitive symptoms.

show abstract

“…This dysbalance is proposed to eventually lead to a disconnection of critical cortico-cortical and cortico-subcortical projection systems, although the underlying mechanisms are not fully understood. 9 No effective pharmacological treatment is available for negative and cognitive symptoms. 8 …”

Section: Introductionmentioning

confidence: 99%

Studying and modulating schizophrenia-associated dysfunctions of oligodendrocytes with patient-specific cell systems

Raabe¹,

Galinski²,

Papiol

et al. 2018

npj Schizophr

Self Cite

View full text Add to dashboard Cite

Postmortem studies in patients with schizophrenia (SCZ) have revealed deficits in myelination, abnormalities in myelin gene expression and altered numbers of oligodendrocytes in the brain. However, gaining mechanistic insight into oligodendrocyte (OL) dysfunction and its contribution to SCZ has been challenging because of technical hurdles. The advent of individual patient-derived human-induced pluripotent stem cells (hiPSCs), combined with the generation of in principle any neuronal and glial cell type, including OLs and oligodendrocyte precursor cells (OPCs), holds great potential for understanding the molecular basis of the aetiopathogenesis of genetically complex psychiatric diseases such as SCZ and could pave the way towards personalized medicine. The development of neuronal and glial co-culture systems now appears to enable the in vitro study of SCZ-relevant neurobiological endophenotypes, including OL dysfunction and myelination, with unprecedented construct validity. Nonetheless, the meaningful stratification of patients before the subsequent functional analyses of patient-derived cell systems still represents an important bottleneck. Here, to improve the predictive power of ex vivo disease modelling we propose using hiPSC technology to focus on representatives of patient subgroups stratified for genomic and/or phenomic features and neurobiological cell systems. Therefore, this review will outline the evidence for the involvement of OPCs/OLs in SCZ in the context of their proposed functions, including myelination and axon support, the implications for hiPSC-based cellular disease modelling and potential strategies for patient selection.

show abstract

Pathophysiology of Schizophrenia

Cited by 14 publications

References 237 publications

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls

Oligodendrocytes as A New Therapeutic Target in Schizophrenia: From Histopathological Findings to Neuron-Oligodendrocyte Interaction

Studying and modulating schizophrenia-associated dysfunctions of oligodendrocytes with patient-specific cell systems

Contact Info

Product

Resources

About