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.

Antipsychotics-Induced Changes in Synaptic Architecture and Functional Connectivity: Translational Implications for Treatment Response and Resistance

“…The extent to which antipsychotics modulate receptor activity is essential to ensure proper processes of neurite outgrowth, synaptogenesis, and spine organization [ 65 ]. In this framework, antipsychotics have shown a different capability to regulate PSD composition and spine architecture by exhibiting different pharmacodynamic profiles and acting through epigenetic mechanisms [ 65 , 66 , 67 , 68 , 69 ]. Specifically, aripiprazole and clozapine were found to increase PSD-95 protein levels, the number of dendritic spines, and the number of PSD puncta in cortical neuron cultures [ 70 ].…”

Canonical and Non-Canonical Antipsychotics’ Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia

“…Preclinical studies in mice showed that maternal immune activation affects dopamine receptor expression, increasing dopamine levels in the striatum and decreasing D2R levels in adult offspring [ 434 , 435 ]. Alterations in cytokine homeostasis may correlate with the pathogenesis of schizophrenia, probably with a link to alterations in dopaminergic and glutamatergic signaling [ 435 ]. IL-1β appears to result in abnormal glutamate release and subsequent neurotransmitter accumulation that induces neuronal death [ 436 ].…”

“…Fernandez-Egea et al showed that patients affected by schizophrenia have increased numbers of natural killer cells, naïve B cells, memory T cells, and monocytes and decreased numbers of dendritic cells, regulatory T cells, and CD4 + T cells in the blood [ 470 ]. Typical antipsychotics decrease the plasma levels of IL-6 and IL-6 receptor (IL-6R) [ 471 ], while atypical antipsychotics, such as clozapine and risperidone, increase the concentrations of IL-2R, IL-6, and TNF-α [ 435 , 472 , 473 ]. Clozapine has been demonstrated to interfere with multiple steps of the inflammatory response [ 474 ] and inhibit microglial activation [ 475 ].…”

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

“…Apart from and beyond their action at dopaminergic and other central receptors, antipsychotic treatment has been demonstrated to modify brain expenditure energy metabolism and impact mitochondria function [ 24 , 25 , 26 ]. The relevance of regulating mitochondrial functions lies in the possible modulation of antioxidant intracellular pathways and other mechanisms involved in cell viability and survivance [ 26 , 27 , 28 ]. The potential modulation of mitochondria function and oxidative stress by antipsychotics is in line with a role for oxidative stress in schizophrenia and related psychosis [ 29 , 30 , 31 , 32 ].…”