13C NMRS of animal models of schizophrenia  

Abstract

Altered brain metabolism is implicated in several brain disorders such as schizophrenia. Insights into underlying mechanisms and how they are altered could help find new treatment strategies.

Animal models serve as tools to mimic human diseases. However, recreating the “normal” course of human disease in animals is difficult. Nevertheless, animal models have shown to be useful in providing knowledge about pathological processes. In this thesis several animal models of brain disorders were used. We used both pharmacological interventions mimicking one feature of schizophrenia, and a gene knock out model aimed at elucidating the role of GAD65 in disease. GABA metabolism is believed to be altered in several brain disorders. Two different protocols for studying the effect of MK-801 were used to mimic schizophrenia, repeated low dose (0.1 mg/kg) MK-801 and repeated high dose injections (0.5 mg/kg) MK-801 respectively. These models were used to gain knowledge about how altered neurotransmitter homeostasis possibly can lead to psychiatric disease.

In paper I, repeated low dose MK-801 injections caused hypermetabolism of glucose and increased glutamatergic activity in the temporal areas only. Thus, it appears that this model does not show the same pattern as seen in patients with schizophrenia but rather mimics the toxic effects of MK-801 possibly caused by increased glutamate release into the synaptic cleft. Repeated injections of high doses of MK-801 (paper II) led to hypometabolism of glucose. It was further shown that perturbation of NMDA receptor function in the model of repeated injections of MK-801 caused changes not only in the glutamatergic and GABAergic systems, but also in that of dopamine. Changes were most pronounced in the frontal cortex (FCX) in analogy with the human condition. In paper II, repeated injection of high doses of MK-801 resulted in increased amounts of glutamate. However, reduced 13C labelling was observed in the same study, which might indicate a transition to reduced glutamate metabolism, and glutamate amounts seen in patients with chronic schizophrenia. In paper III, also using injection of repeated high doses of MK-801, we found similar results as in paper II, with reduced 13C labelling in glutamate and glutamine. Further we found reduced 13C labelling in GABA, lactate and NAA implying neuronal hypometabolism

In paper IV studying GAD65 knockout mice, labelling from glucose was dramatically decreased in lactate and alanine reflecting attenuated glycolysis. In concurrence with this TCA cycle activity, was decreased in the GAD65 knockout animals. Consequently, decreased 13C labelling in GABA was observed, implying neuronal hypometabolism.

Patients with schizophrenia constitute a heterogeneous group with a large variety of symptoms and it is likely that the underlying causes of psychosis are not always induced by the same mechanisms. Still, it is of great interest that blocking of the NMDA receptor using repeated injections of high doses of MK-801 caused neuronal hypometabolism as found in the GAD65 knockout model. Hypometabolism in FCX is a common finding in patients with schizophrenia.