Glial–Neuronal Interactions are Impaired in the Schizophrenia Model of Repeated MK801 Exposure

Abstract

Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

Hypermetabolic State in the 7-Month-Old Triple Transgenic Mouse Model of Alzheimer'S Disease and the Effect of Lipoic Acid: A 13C-NMR Study

“…13 C glucose or acetate cycling ratio in terms of glutamate or glutamine gives information about how long does the 13 C label derived from [1-13 C]glucose and [1,2-13 C]acetate stays in the TCA cycle before being incorporated into glutamate or glutamine; e.g., 13 C glucose cycling ratio in terms of glutamate means how long does the 13 C label derived from [1-13 C]glucose stays in the TCA cycle before being incorporated into glutamate. 23 Approximately 100% increase of cycling ratio from glucose and acetate in terms of glutamate were also observed in the 3xTg-AD mice (Figures 5Bi and 5Ci). The results in this study suggest that the 13 C label turns over faster in the TCA cycle of 7-month-old 3xTg-AD mice.…”

“…23 A large fraction of the glutamate and GABA present in the neurons is synthesized from glutamine transferred from astrocytes. Using the data of glutamine labeled specifically in the astrocytes (from [1,2-13 C]acetate) and comparing it with the similarly labeled glutamate, the transfer ratio between astrocytes and neurons may be calculated.…”

“…[21][22][23] We calculated the glycolytic activity, 22 TCA cycle activity, 21 13 C glucose, and acetate cycling ratio in terms of glutamate and glutamine, 23 and transfer ratio from astrocytes to neurons. 22 …”

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

“…Proton decoupled 13 C-MRS spectra were obtained using a Bruker DRX-400 spectrometer (Bruker Analytik GmbH, Germany) and the number of scans was 25,000. (20).…”

“…A previously protocol described (20) was used. Briefly, VGLUT1+/-and WT mice (n= 8/group) received [1-13 C]glucose (543 mg/kg i.p.)…”