Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia

Uranova, N.A.; Vikhreva, Olga; Rakhmanova, V. I.

doi:10.1016/j.ajp.2021.102752

Cited by 21 publications

(14 citation statements)

References 43 publications

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“…It should be noted that microglial dystrophy has been proposed to contribute to the pathogenesis of schizophrenia and progress during the disease, resulting in a subsequent increase in oxidative stress and mitochondrial dysfunctions [ 5 , 166 ]. Moreover, microglia activation following maternal poly(I:C) challenges may be more pronounced in male than female offspring, mirroring the higher incidence of schizophrenia in males as well as more severe clinical features [ 167 , 168 ]. Proteomic analysis of poly(I:C)-treated rodents showed significant changes in the protein expression of 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) and collapsin response mediator protein 5 (CRMP5) [ 160 ].…”

Section: Animal Inflammatory Models Of Schizophreniamentioning

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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Section: Animal Inflammatory Models Of Schizophreniamentioning

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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“…Post-mortem analysis is an important tool to identify and characterize changes in microglia that are not possible to detect in live patients, although one must be aware of important confounding factors, namely the cause of death, co-morbidities, medication, lack of knowledge of disease stage, and/or symptoms predominance, to mention a few. Some studies do not mention the stage or the predominant symptomatology and only refer the involvement of patients with a diagnosis [65,[81][82][83] or chronic schizophrenia [84][85][86][87][88]. The lack of information about disease staging led us to organize post-mortem data by brain region (as a summary, please see Table 2).…”

Section: Schizophrenia-associated Microglia Alterations Revealed By P...mentioning

confidence: 99%

Microglia sequelae: brain signature of innate immunity in schizophrenia

2022

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Schizophrenia is a psychiatric disorder with significant impact on individuals and society. The current pharmacologic treatment, which principally alleviates psychosis, is focused on neurotransmitters modulation, relying on drugs with severe side effects and ineffectiveness in a significant percentage of cases. Therefore, and due to difficulties inherent to diagnosis and treatment, it is vital to reassess alternative cellular and molecular drug targets. Distinct risk factors – genetic, developmental, epigenetic, and environmental – have been associated with disease onset and progression, giving rise to the proposal of different pathophysiological mechanisms and putative pharmacological targets. Immunity is involved and, particularly microglia – innate immune cells of the central nervous system, critically involved in brain development – have captured attention as cellular players. Microglia undergo marked morphologic and functional alterations in the human disease, as well as in animal models of schizophrenia, as reported in several original papers. We cluster the main findings of clinical studies by groups of patients: (1) at ultra-high risk of psychosis, (2) with a first episode of psychosis or recent-onset schizophrenia, and (3) with chronic schizophrenia; in translational studies, we highlight the time window of appearance of particular microglia alterations in the most well studied animal model in the field (maternal immune activation). The organization of clinical and translational findings based on schizophrenia-associated microglia changes in different phases of the disease course may help defining a temporal pattern of microglia changes and may drive the design of novel therapeutic strategies.

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“…Some pathophysiological circumstances, however, result in microglial activation, which is mediated by a wide array of cellular mechanisms [ 33 ]. Dynamic changes in microglial activity have also been reported in the course of schizophrenia, although their etiopathogenesis has not yet been conclusively explained [ 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

Chamera

Curzytek

Kamińska

et al. 2022

Cells

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The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances.

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Abnormal microglial reactivity in gray matter of the prefrontal cortex in schizophrenia

Cited by 21 publications

References 43 publications

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

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

Microglia sequelae: brain signature of innate immunity in schizophrenia

Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats

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