Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology

Silva, Tânia Maria Sarmento; Guma, Elisa; Hafizi, Sina; Koppel, Alex; Rusjan, Pablo; Kennedy, James L.; Chakravarty, M. Mallar; Mizrahi, Romina

doi:10.1016/j.biopsych.2021.06.021

Cited by 13 publications

(11 citation statements)

References 51 publications

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“…Immune-mediated excessive synaptic pruning has been proposed as one possibility [ 130 , 131 ]. Supporting this, numerous post-mortem studies have demonstrated increased density of microglial cells (with a hypertrophic morphology indicating an activated phenotype) in the brains of schizophrenia patients compared with healthy controls, particularly in the frontal and temporal lobes [ 130 , 132 – 134 ]. Microglial cells are the immune cells of the central nervous system, which play a major role in synaptic pruning and phagocytosis of synaptic material in the brain [ 135 , 136 ].…”

Section: Discussionmentioning

confidence: 90%

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Howes

Cummings

Chapman

et al. 2022

Neuropsychopharmacol.

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Over the last five decades, a large body of evidence has accrued for structural and metabolic brain alterations in schizophrenia. Here we provide an overview of these findings, focusing on measures that have traditionally been thought to reflect synaptic spine density or synaptic activity and that are relevant for understanding if there is lower synaptic density in the disorder. We conducted literature searches to identify meta-analyses or other relevant studies in patients with chronic or first-episode schizophrenia, or in people at high genetic or clinical risk for psychosis. We identified 18 meta-analyses including over 50,000 subjects in total, covering: structural MRI measures of gyrification index, grey matter volume, grey matter density and cortical thickness, neurite orientation dispersion and density imaging, PET imaging of regional glucose metabolism and magnetic resonance spectroscopy measures of N-acetylaspartate. We also review preclinical evidence on the relationship between ex vivo synaptic measures and structural MRI imaging, and PET imaging of synaptic protein 2A (SV2A). These studies show that schizophrenia is associated with lower grey matter volumes and cortical thickness, accelerated grey matter loss over time, abnormal gyrification patterns, and lower regional SV2A levels and metabolic markers in comparison to controls (effect sizes from ~ −0.11 to −1.0). Key regions affected include frontal, anterior cingulate and temporal cortices and the hippocampi. We identify several limitations for the interpretation of these findings in terms of understanding synaptic alterations. Nevertheless, taken with post-mortem findings, they suggest that schizophrenia is associated with lower synaptic density in some brain regions. However, there are several gaps in evidence, in particular whether SV2A findings generalise to other cohorts.

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Section: Discussionmentioning

confidence: 90%

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Howes

Cummings

Chapman

et al. 2022

Neuropsychopharmacol.

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“…An additional complicating factor for second-generation radioligands is their susceptibility to genetic polymorphisms responsible for differences in binding affinity that renders necessary prior genotyping of the patients. In spite of such restraints, PET with radioligands targeting the TSPO has been used to detect patterns of neuroinflammation in vivo , assess disease severity and progression, and therapeutic efficacy of anti-inflammatory drugs ( Ottoy et al, 2018 ; Selvaraj et al, 2018 ; Veronese et al, 2018 ; De Picker et al, 2019 ; Schifani et al, 2019 ; Laurikainen et al, 2020 ; Conen et al, 2021 ; Da Silva et al, 2021 ; Marques et al, 2021 ).…”

Section: Limitationmentioning

confidence: 99%

The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects

Laricchiuta,

Papi,

Decandia

et al. 2024

Front. Cell. Neurosci.

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Schizophrenia is a complex and severe mental disorder that affects approximately 1% of the global population. It is characterized by a wide range of symptoms, including delusions, hallucinations, disorganized speech and behavior, and cognitive impairment. Recent research has suggested that the immune system dysregulation may play a significant role in the pathogenesis of schizophrenia, and glial cells, such as astroglia and microglia known to be involved in neuroinflammation and immune regulation, have emerged as potential players in this process. The aim of this systematic review is to summarize the glial hallmarks of schizophrenia, choosing as cellular candidate the astroglia and microglia, and focusing also on disease-associated psychological (cognitive and emotional) changes. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed, Scopus, and Web of Science for articles that investigated the differences in astroglia and microglia in patients with schizophrenia, published in the last 5 years. The present systematic review indicates that changes in the density, morphology, and functioning of astroglia and microglia may be involved in the development of schizophrenia. The glial alterations may contribute to the pathogenesis of schizophrenia by dysregulating neurotransmission and immune responses, worsening cognitive capabilities. The complex interplay of astroglial and microglial activation, genetic/epigenetic variations, and cognitive assessments underscores the intricate relationship between biological mechanisms, symptomatology, and cognitive functioning in schizophrenia.

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“…The hypothesis proposes that glia are activated by environmental risk factors, such as stress. There is evidence for higher levels of markers associated with an activated glial phenotype in schizophrenia relative to controls from post-mortem studies (effect size ~0.7 on meta-analysis) [166], and that greater PET signal for TSPO, a protein expressed by activated glia, is associated with greater predicted complement levels in patients [84]. However, there are inconsistencies in the TSPO PET findings in schizophrenia (reviewed in [167]).…”

Section: Gaps In the Evidence And Future Directionsmentioning

confidence: 99%

“…The link between complement expression and brain structure and function has begun to be investigated. A recent imaging genetics study of a mixed sample of healthy control subjects ( n = 46), patients with psychosis ( n = 40) and individuals at clinical high risk for psychosis ( n = 43) showed that levels of genotype-predicted brain C4A expression were positively associated with brain levels of translocator protein (TSPO, a marker expressed by glia), and negatively associated with hippocampal surface area [ 84 ]. However, there was no significant effect of clinical group on these relationships, indicating it is most likely a common mechanism.…”

Section: Genetic and Environmental Risk Factors For Schizophrenia Imp...mentioning

confidence: 99%

The synaptic hypothesis of schizophrenia version III: a master mechanism

Howes

Onwordi

2023

Mol Psychiatry

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The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.

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Genetically Predicted Brain C4A Expression Is Associated With TSPO and Hippocampal Morphology

Cited by 13 publications

References 51 publications

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

Neuroimaging in schizophrenia: an overview of findings and their implications for synaptic changes

The role of glial cells in mental illness: a systematic review on astroglia and microglia as potential players in schizophrenia and its cognitive and emotional aspects

The synaptic hypothesis of schizophrenia version III: a master mechanism

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