CoChat
Sign Up
Cited by 113Tryptophan and brain disordersSchizophrenia research and treatmentNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 325 of the 325 references it cites were found in a registry or an index.

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

Open access
de Bartolomeis, Andrea, Barone, Annarita, Vellucci, Licia, Mazza, Benedetta, Austin, Mark C., Iasevoli, Felice, Ciccarelli, Mariateresa·2022·Molecular Neurobiology
DOI 10.1007/s12035-022-02976-3PMC PMC9463235
Open this paper in CoChat — free accountOpen PDF

Abstract

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s12035-022-02976-3

Cites

325 of 325 references verified0 citation errors · 0 not checkable

Statistics

Figures

Fig. 1 PRISMA flow diagram showing the flow of information through the different phases of the systematic review
Fig. 1 PRISMA flow diagram showing the flow of information through the different phases of the systematic reviewCC BY · PubMed Central
Fig. 2 Potential role of inflammation in schizophrenia pathogenesis: Inflammation-induced immune alteration may represent a common pathway for environmental and genetic risk factors in schizophrenia, resulting in aberration of synaptic plasticity. SCZ (schizophrenia); ROS (reactive oxidative species); RNS (nitrosative species); NO (nitric oxide); NKA (Na + /K + -ATPase); TBARS (thiobarbituric acid-reactive substances); PCC (protein carbonyl content); C4 (complement component 4); AP-1 (activator protein 1); TNF-α (tumor necrosis factor α); IL-1β (interleukin 1β); IL-1 (interleukin 1); IL-6 (interleukin 6); CFS (cerebrospinal fluid); IL-2(interleukin 2); IFN-γ (interferon γ); IL-10 (interleukin 10); IL-12 (interleukin 12); IL-17 (interleukin 17); IL-10 (interleukin 10); TGF-β (transforming growth factor β). Created with BioRender.com
Fig. 2 Potential role of inflammation in schizophrenia pathogenesis: Inflammation-induced immune alteration may represent a common pathway for environmental and genetic risk factors in schizophrenia, resulting in aberration of synaptic plasticity. SCZ (schizophrenia); ROS (reactive oxidative species); RNS (nitrosative species); NO (nitric oxide); NKA (Na + /K + -ATPase); TBARS (thiobarbituric acid-reactive substances); PCC (protein carbonyl content); C4 (complement component 4); AP-1 (activator protein 1); TNF-α (tumor necrosis factor α); IL-1β (interleukin 1β); IL-1 (interleukin 1); IL-6 (interleukin 6); CFS (cerebrospinal fluid); IL-2(interleukin 2); IFN-γ (interferon γ); IL-10 (interleukin 10); IL-12 (interleukin 12); IL-17 (interleukin 17); IL-10 (interleukin 10); TGF-β (transforming growth factor β). Created with BioRender.comCC BY · PubMed Central
Fig. 3 Overview of the oxidative stress and immune alterations influence on tripartite synapse in schizophrenia. Chronic oxidative stress may trigger multiple intracellular changes responsible for the increase in neuronal Ca2 + influx and therefore accumulation of ROS and RNS, disrupting synaptic transmission. The action of immune response on glial cells can cause an impairment of glutamate reuptake, inducing a further enhancing of neuronal Ca2 + influx, while in neurons can directly alter the membrane delivery of the AMPAR and NMDAR. KYNA and QUIN, the neuroactive metabolites of TRP/KYNA pathway, act as NMDAR antagonists and agonists, respectively. Following the glutamatergic hypothesis of schizophrenia, has been suggested the imbalance in KYNA pathway, promoting the production of KINA over QUIN resulting in microglial activation and KINA-mediated neurotoxicity. Moreover, GABAergic inhibitory interneurons dysfunction may induce a glutamate storm from excitatory glutamatergic cortical pyramidal neurons and a subcortical dopamine storm. GABA (γ-aminobutyric acid); TRP (tryptophan); IDO (indoleamine 2,3-dioxygenase); KIN (kynurenine); KINA (kynurenic acid); QUIN (quinolinic acid); ROS (reactive oxidative species); RNS (nitrosative species). Created with BioRender.com
Fig. 3 Overview of the oxidative stress and immune alterations influence on tripartite synapse in schizophrenia. Chronic oxidative stress may trigger multiple intracellular changes responsible for the increase in neuronal Ca2 + influx and therefore accumulation of ROS and RNS, disrupting synaptic transmission. The action of immune response on glial cells can cause an impairment of glutamate reuptake, inducing a further enhancing of neuronal Ca2 + influx, while in neurons can directly alter the membrane delivery of the AMPAR and NMDAR. KYNA and QUIN, the neuroactive metabolites of TRP/KYNA pathway, act as NMDAR antagonists and agonists, respectively. Following the glutamatergic hypothesis of schizophrenia, has been suggested the imbalance in KYNA pathway, promoting the production of KINA over QUIN resulting in microglial activation and KINA-mediated neurotoxicity. Moreover, GABAergic inhibitory interneurons dysfunction may induce a glutamate storm from excitatory glutamatergic cortical pyramidal neurons and a subcortical dopamine storm. GABA (γ-aminobutyric acid); TRP (tryptophan); IDO (indoleamine 2,3-dioxygenase); KIN (kynurenine); KINA (kynurenic acid); QUIN (quinolinic acid); ROS (reactive oxidative species); RNS (nitrosative species). Created with BioRender.comCC BY · PubMed Central
Fig. 4 MIA rodent models are based on the observation that immune challenges experienced by the mother during gestation can exert inflammatory responses which disrupt fetal neurodevelopmental processes. In particular, MIA results in a wide range of neurochemical, histopathological, and behavioral alterations in the offspring that recapitulate the pathophysiology of schizophrenia. GD 8.5 (gestational day 8.5); GD 18.5 (gestational day 18.5); IL-6 (interleukin 6); SCZ (schizophrenia); PV + (parvalbumin-positive); NMDAR (N-methyl-D-aspartate receptor); PFC (prefrontal cortex); PPI (pre-pulse inhibition). Created with BioRender.com
Fig. 4 MIA rodent models are based on the observation that immune challenges experienced by the mother during gestation can exert inflammatory responses which disrupt fetal neurodevelopmental processes. In particular, MIA results in a wide range of neurochemical, histopathological, and behavioral alterations in the offspring that recapitulate the pathophysiology of schizophrenia. GD 8.5 (gestational day 8.5); GD 18.5 (gestational day 18.5); IL-6 (interleukin 6); SCZ (schizophrenia); PV + (parvalbumin-positive); NMDAR (N-methyl-D-aspartate receptor); PFC (prefrontal cortex); PPI (pre-pulse inhibition). Created with BioRender.comCC BY · PubMed Central
Fig. 5 Neuroinflammatory responses in schizophrenia lead to abnormalities in the GABA system due to oxidative stress and hypermethylation in the promoter region of GABA-synthesizing enzymes. Reduced cortical GABA inhibition contributes, in turn, to overstimulation of downstream glutamatergic and dopaminergic neurons. GABA (γ-aminobutyric acid); GAD-65 (glutamic acid decarboxylase 65); GAD-67 (glutamic acid decarboxylase 67); ROS (reactive oxidative species); PV (parvalbumin); GAT (GABA transporter). Created with BioRender.com
Fig. 5 Neuroinflammatory responses in schizophrenia lead to abnormalities in the GABA system due to oxidative stress and hypermethylation in the promoter region of GABA-synthesizing enzymes. Reduced cortical GABA inhibition contributes, in turn, to overstimulation of downstream glutamatergic and dopaminergic neurons. GABA (γ-aminobutyric acid); GAD-65 (glutamic acid decarboxylase 65); GAD-67 (glutamic acid decarboxylase 67); ROS (reactive oxidative species); PV (parvalbumin); GAT (GABA transporter). Created with BioRender.comCC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 325 references

Research works printed but not linked: 2

  1. Li R, Ma X, Wang G, Yang J, Wang C (2016) Why sex differences in schizophrenia? J transl neuroscience 1(1):37–42
  2. Müller N 2010 COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Current opinion in investigational drugs (London, England : 2000) 11 (1):31–42

Cited by

Sorted by citations

Related

See all

Metadata

Authors
de Bartolomeis, A., Barone, A., Vellucci, L., Mazza, B., Austin, M. C., Iasevoli, F., & Ciccarelli, M.
Affiliations
  • Federico II University Hospital (IT)
  • Idaho State University (US)
ORCID
Venue
Molecular Neurobiology
Publisher
Springer Science and Business Media LLC
Published
2022-08-13
Volume
59
Issue
10
Pages
6460-6501
ISSN
  • 0893-7648 (ISSN-L)
  • 1559-1182
DOI
10.1007/s12035-022-02976-3
PMC
PMC9463235
OpenAlex
W4291237996
Cited by
113
References
325
Citations by year
2026: 31 · 2025: 30 · 2024: 33 · 2023: 15 · 2022: 4
FWCI
1.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurobiology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Università degli Studi di Napoli Federico II
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
schizophrenia, inflammation, dopamine-glutamate interaction, dendritic spines, postsynaptic density, NMDA receptor, microglia, maternal immune activation, kynurenine pathway, plasma inflammatory markers, functional connectivity, cognitive impairment, antipsychotic resistance, clozapine, translational research
MeSH terms
Dopamine, Humans, Inflammation, Schizophrenia, Antipsychotic Agents, Receptors, N-Methyl-D-Aspartate, Glutamic Acid

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review