Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study

Abstract

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R > L), whereas the opposite relationship (R < L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders.

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

“…First, when considering canonical and non-canonical mechanisms of antipsychotics focusing on dopamine, it is probably a reductionistic approach for drugs that have a complex receptor profile. Despite the significant role of other neurotransmitter systems, above all, the glutamatergic [ 572 , 573 ], GABAergic [ 574 ], and serotoninergic [ 82 ] ones; dopamine remains a pivotal target for schizophrenia treatment [ 575 , 576 ]. Furthermore, the search for dopamine-based non-canonical mechanisms is particularly timing considering the emerging novel concepts on dopamine molecular anatomy [ 577 ] and physiology relevant for the pathophysiology and clinics of salience and cognition mechanisms [ 578 ], possibly involved in the clinical manifestations of schizophrenia, especially in terms of abnormal cortical-subcortical connectivity [ 579 ].…”

Retinal electrophysiology in central nervous system disorders. A review of human and mouse studies

“…One mechanism proposed was that an increased inhibition through GABA signaling of the horizontal cells could reduce both the a-and b-wave amplitudes through inhibition of the photoreceptors and bipolar cells (Demmin et al, 2018;Hébert et al, 2020). An imbalance between GABA and glutamate neurotransmitters in the prefrontal cortex (Mayeli et al, 2022) and thalamus (Quiñones et al, 2021) has been implicated in schizophrenia which lends support for the suggested GABAergic influence on the ERG by horizontal cells.…”

N-Acetylaspartate and Choline Metabolites in Cortical and Subcortical Regions in Clinical High Risk Relative to Healthy Control Subjects: An Exploratory 7T MRSI Study

“…The use of magnetic resonance spectroscopic imaging (MRSI) allows the acquisition of data from multiple voxels simultaneously [29][30][31]. Compared to single-voxel MRS, which is limited to acquiring data from a single brain region at a time, spectral data from MRSI can be from a single slice, multiple slices, or multiple volumes simultaneously [31].…”