Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia

Abstract

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Prefrontal GABA Levels Measured With Magnetic Resonance Spectroscopy in Patients With Psychosis and Unaffected Siblings

“…This ratio finding might be determined by the trend for creatine/water to be higher especially in untreated patients than in healthy controls (for effect sizes, see Table S6 in the data supplement). These data are generally consistent with several studies of GABA levels in the prefrontal cortex (10,11,15,17), in the occipital cortex (13,14,17), and in the hippocampal formation (12), which found GABA levels to be reduced or unchanged in patients with schizophrenia compared with healthy controls. However, our findings differ in directionality from those by Ongür et al (20) in the dorsal anterior cingulate and Kegeles et al (19) in the medial prefrontal cortex (see the Supplementary Discussion section in the data supplement).…”

“…While some studies (10)(11)(12) found no differences in patients with schizophrenia compared with healthy controls, others found reduced levels in the occipital (13,14) and prefrontal (15) cortices (including the dorsal anterior cingulate cortex in patients over 35 years of age [16]) and in the basal ganglia (17). In contrast, our preliminary data in a small group of patients who do not overlap with the ones presented here (18) showed elevated GABA levels in the dorsal anterior cingulate in treated patients with psychosis compared with healthy controls.…”

Glutamatergic and Neuronal Dysfunction in Gray and White Matter: A Spectroscopic Imaging Study in a Large Schizophrenia Sample

“…[26][27][28][29][30] However, the quality of the spectral fits is not always clear in these reports (except for [27][28][29] ) and the samples were small (9 to 30 for the schizophrenia groups 6 ). More recent studies reported increases, [31][32][33][34][35] reductions 25,[36][37][38] and no differences 39 in Glx or glutamate. Two 33,34 of the 5 recent studies documenting elevations involved more ventral regions.…”

MK-801-induced impairments on the trial-unique, delayed nonmatching-to-location task in rats: effects of acute sodium nitroprusside

“…This impairment may be attributed to more basic visual discrimination and recognition deficits (Martinelli and Shergill 2015). Pattern separation is dependent upon the dentate gyrus, a hippocampus region with altered functioning and reduced volume in schizophrenia (Haukvik et al 2015;Faghihi and Moustafa 2015;Stan et al 2015). Taken together, working memory and pattern separation are cognitive domains impaired in schizophrenia that may reduce patient quality of life.…”