Glutamatergic Deficits in Schizophrenia – Biomarkers and Pharmacological Interventions within the Ketamine Model

Abstract

Background: The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. NMDAR hypofunction can explain many schizophrenia symptoms directly due to excitatory-to-inhibitory (E/I) imbalance, but also dopaminergic dysfunction itself. However, so far no new drug targeting the NMDAR has been successfully approved. In the search for possible biomarkers it is interesting that ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) and functional magnetic resonance imaging (fMRI) signals.Methods: We systematically searched PubMed/Medline and Web of Knowledge databases (January 2006 to July 2017) to identify EEG/MEG and fMRI studies of the ketamine model of schizophrenia with human subjects. The search strategy identified 209 citations of which 46 articles met specified eligibility criteria.Results: In EEG/MEG studies, ketamine induced changes of event-related potentials, such as the P300 potential and the mismatch negativity, similar to alterations observed in schizophrenia patients. In fMRI studies, alterations of activation were observed in different brain regions, most prominently within the anterior cingulate cortex and limbic structures as well as task-relevant brain regions. These alterations were accompanied by changes in functional connectivity, indicating a balance shift of the underlying brain networks. Pharmacological treatments did alter ketamine-induced changes in EEG/MEG and fMRI studies to different extents.Conclusion: This review highlights the potential applicability of the ketamine model for schizophrenia drug development by offering the possibility to assess the effect of pharmacological agents on schizophrenia-like symptoms and to find relevant neurophysiological and neuroimaging biomarkers.

Modulating NMDA receptors to treat MK-801-induced schizophrenic cognition deficit: effects of clozapine combining with PQQ treatment and possible mechanisms of action

“…At the same time, convergent evidence shows that the expression of GSK-3β and its related signaling pathways have changed in individuals affected by schizophrenia [34]. In addition, several different atypical antipsychotic drugs have been reported to increase the inhibitory phosphorylation of GSK-3β in brain regions of rats [35][36][37][38]. Furthermore, some other studies have reported a high correlation between Akt gene variants and schizophrenia [39,40].…”

Cortical Microcircuit Mechanisms of Mismatch Negativity and Its Underlying Subcomponents

“…An additional advantage presented by animal models is that virtually all experimental practices employed in human studies have homologs for animal experimentation, allowing for direct comparison while simultaneously offering more mechanistic insight. For instance, ketamine, along with another N-methyl-D-aspartate receptor (NMDAR) antagonists, is known to reduce the MMN in humans as well as rodents and non-human primates (Ehrlichman et al, 2008;Gil-Da-Costa et al, 2013;Chen et al, 2015;Haaf et al, 2018;Schuelert et al, 2018). Furthermore, the oddball task applies to a wide variety of experimental assays in animal research.…”

“…One point to consider in this problem is that NMDAR blockade, a face-valid model of SZ sensory processing features, also reduces MMN in humans and animals (Ehrlichman et al, 2008;Gil-Da-Costa et al, 2013;Haaf et al, 2018;Schuelert et al, 2018). The nature of how NMDAR blockade affects the time-course and oscillatory aspects of auditory MMN has led to the interpretation that DD specifically is NMDAR-dependent (Javitt et al, 1996;Lee et al, 2018).…”

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms

“…Deactivation was observed in a number of BOLD rs‐fMRI studies in the subgenual anterior cingulate cortex (SgACC) and the medial orbitofrontal cortex . Considering functional connectivity (seed‐based or global brain connectivity/GBC), generally, an increased pattern of connectivity was observed by most authors (for a review see Maltbie et al and Haaf et al). Shortly, Höflich observed hyperconnectivity between the thalamus and both parietal and temporal cortex; Dandash reported increased FC of the striatum, thalamus, midbrain and PFC; Driesen also observed elevated FC of the thalamus and striatum; and Fleming reported increased FC between the frontal pole, ACC, PCC and insula.…”