Microglial Activation and the Onset of Psychosis

Cannon, Tyrone D.

doi:10.1176/appi.ajp.2015.15111377

Cited by 12 publications

(5 citation statements)

References 10 publications

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“…Microglial activation in clinical high risk S Hafizi et al that showed higher DVR in CHR and patients with chronic schizophrenia, as compared to healthy volunteers (Bloomfield et al, 2015). However, there are several differences between our study and Bloomfield and colleagues study, particularly the use of an alternative outcome measure, which for radioligands without a reference region is always controversial (Cannon, 2015;Narendran and Frankle, 2016). Notably in the Bloomfield et al [ 11 C]PBR28 study, using the validated V T with 2TCM (Fujita et al, 2008), the authors did not find any significant difference in microglial activation between CHR/ chronic schizophrenia and healthy volunteers.…”

Section: Discussionmentioning

confidence: 56%

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Hafizi

Silva

Gerritsen

et al. 2017

Neuropsychopharmacol.

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Several lines of evidence implicate microglial activation and abnormal immune response in the etiology of psychosis. Previous positron emission tomography (PET) neuroimaging studies of the translocator protein 18 kDa, TSPO, were limited by low affinity of the first-generation radioligand, low-resolution scanners, and small sample sizes. Moreover, there is a dearth of literature on microglial activation in individuals at clinical high risk (CHR) for psychosis. We used a novel second-generation TSPO radioligand, [F]FEPPA, to examine whether microglial activation is elevated in the dorsolateral prefrontal cortex (DLPFC) and hippocampus of antipsychotic-naive CHR. Twenty-four CHR (antipsychotic-naive n=22) and 23 healthy volunteers (HV) completed a high resolution [F]FEPPA PET scan and MRI. The PET data were analyzed using the validated two-tissue compartment model with arterial plasma input function with total volume of distribution (V) as outcome measure. All analyses were controlled for the TSPO rs6971 polymorphism. We did not observe any significant differences in microglial activation, as indexed by [F]FEPPA V, between CHR and HV in either the DLPFC (F=0.41, p=0.52) or the hippocampus (F=2.78, p=0.10). Exploratory associations show that in CHR, [F]FEPPA V was positively correlated with apathy (DLPFC: r=0.55, p=0.008; hippocampus: r=0.52, p=0.013) and state anxiety (DLPFC: r=0.60, p=0.003; hippocampus: r=0.48, p=0.024). The lack of significant group differences in [F]FEPPA V suggests that microglial activation is not significantly elevated in the clinical high risk state that precedes psychosis.

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Section: Discussionmentioning

confidence: 56%

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Hafizi

Silva

Gerritsen

et al. 2017

Neuropsychopharmacol.

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“…On the other hand, dysregulation of cortical functions can result in disinhibition of the subcortical dopaminergic system, thus promoting the emergence of positive psychotic symptoms in schizophrenia [ 2 ]. Therefore, dysregulated microglia may contribute to the decline of gray matter and altered functional connectivity observed in schizophrenia, plausibly through pruning of weak synapses [ 96 ]. In this framework, targeting regulators of microglia activation would be indicated as a potential early therapeutic strategy in treating schizophrenia [ 97 ].…”

Section: Molecular Abnormalities Driven By Inflammatory Events Releva...mentioning

confidence: 99%

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Bartolomeis¹,

Barone²,

Vellucci³

et al. 2022

Mol Neurobiol

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Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the “quantal” elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.

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“…MIA models involving cytokine network dysfunction culminate in microglia activation, impacting glial cell survival and contributing to morphological and functional changes in the brain [ 87 , 88 ]. Microglia activation leads to a mechanism by which both immunological and neuroplasticity-related factors via the elimination of weak or inactive synapses contribute to gray matter decline and altered functional connectivity reminiscent of schizophrenia [ 53 , 66 , 89 ]. Consistent with these findings, the activation of microglia leads to structural changes at the PSD and altered expression of genes involving NMDAR-dependent plasticity by decreasing the density of spines and synapses of glutamatergic cortical pyramidal neurons below the critical threshold for neural network functioning [ 90 , 91 ].…”

Section: Molecular Abnormalities Driven By Inflammation and Oxidative...mentioning

confidence: 99%

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

et al. 2023

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Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants’ mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.

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Microglial Activation and the Onset of Psychosis

Cited by 12 publications

References 10 publications

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Imaging Microglial Activation in Individuals at Clinical High Risk for Psychosis: an In Vivo PET Study with [18F]FEPPA

Linking Inflammation, Aberrant Glutamate-Dopamine Interaction, and Post-synaptic Changes: Translational Relevance for Schizophrenia and Antipsychotic Treatment: a Systematic Review

Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

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