Ex vivo ¹H-MRS brain metabolic profiling in a two-hit model of schizophrenia-related alterations: effects of prenatal immune activation and peripubertal stress

Abstract

Prenatal infections are environmental risk factors for neurodevelopmental disorders. In addition, traumatic experiences during adolescence in individuals exposed to infections during gestation could increase the risk of schizophrenia. Given the tremendous burden that these diseases pose on societies when they fully manifest, it is of the most crucial importance to discover potential markers of the disease in its early stages or even before its onset, so that therapeutic strategies may be implemented. In the present study, we combined a well-characterized two-hit model of schizophreniarelated symptoms with proton magnetic resonance spectroscopy to discover potential biomarkers. To this end, we i.p. injected 100 µg/kg/ml of lipopolysaccharide (LPS) or saline on gestational days 15 and 16 to pregnant rats. Their male offspring were then subjected to five episodes of stress or handling on alternate days during postnatal days (PND) 28 to 38. Once the animals reached adulthood (PND70), we evaluated prepulse inhibition (PPI). At PND90, we performed an ex vivo proton magnetic resonance spectroscopy study in the cortex and striatum. While we did not detect alterations in PPI at the age tested, we found neurochemical disturbances induced by LPS, stress or (more interestingly) their interaction. LPS decreased glucose levels in the cortex and striatum and altered glutamate, glutamine and N-acetylaspartate levels. Glutamate and glutamine levels in the left (but not right) striatum were differentially affected by prenatal LPS exposure in a manner that depended on stress experiences. These results suggest that alterations in the glutamate cycle in the striatum may predate the full emergence of disorders of the schizophrenic spectrum and could be used as early markers of the disease.