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

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.

Keywords: Clozapine; Inflammation; Interleukin; Microglia; Post-synaptic density; Treatment-resistant schizophrenia.

Fig. 1

PRISMA flow diagram showing the flow of information through the different phases of the systematic review

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. 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. 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. 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