Regulation of the GABA cell phenotype in neurodevelopmental model of schizophrenia in rats

Abstract

Introduction: Schizophrenia is a complex disorder resulting from combination of genetic and environmental factors, which increase the risk of the disorder. Recently, it has been suggested that changes in GABAergic transmission, can be component in generation of schizophrenia. Some reports demonstrated changes in neurochemical and histological markers of neuronal subtypes, in particular dysfunction of GABAergic interneurons in schizophrenia. GABA itself is reportedly diminished in hippocampus in schizophrenic patients. However, GABA is not a particularly sensitive marker for GABAergic interneurons, as its concentration increases in post-mortem condition. On the other hand, immunostaining for the enzyme glutamate decarboxylase (GAD) can provide a useful marker for GABA-synthesizing neurons. Calcium-binding proteins (CBS) are other important markers of GABAergic neurons [1]. GABAergic neurons can be defined by the presence of one of three CBPs: parvalbumin, calretinin and calbindin. It has been shown that the major role of CBS consists of buffering and transport of calcium ions as well as protection and regulation of some enzymatic systems [2]. Purpose of the study: The present study was designed to determine the effect of prenatal LPS-treatment on neuronal expression of parvalbumin, GAD67 and number of cartridges in the frontal cortex and hippocampus of adult rats. To verify the used model, rats' performance in behavioral tests was characterized. Next, parvalbumin (PV) and glutamate decarboxylase enzyme (GAD67) immunoreactivity was determined in the cingulate cortex and hippocampal (DG, CA3, CA1) subfields. Methods: Adult female rats were administered with LPS subcutaneously at a dose of 1 mg/kg, in the second and third week of pregnancy. In a set of behavioral studies, we investigated exploration, efficacy of PPI and social interaction in control and in LPS-treated animals. After that we evaluated the number of PV-and GAD67-containing interneurons in cortex and hippocampal subfields in control and LPS-treated animals. Results: The results showed sex-dependent changes in the number of GABAergic interneurons. In females, the number of parvalbumin-and GAD67-immunoreactive neurons dropped in the frontal cortex but no such changes were observed in the hippocampal areas under study. In male offspring of LPS-challenged mothers, a statistically significant reduction of the number of these interneurons was noted in the dentate gyrus and in CA3 and CA1 hippocampal areas but there were no changes in the cingulated cortex. We evaluated also density of chandelier neuron axon terminals (cartridges). The analysis demonstrated a decreased density of parvalbumin positive cells in specific layers (II/III and V/VI) of the cortex in both female and male offspring of LPS-treated mothers. No alterations of cartridges density were detected in the hippocampal areas under study. Conclusion: The obtained results strongly support existence of GABAergic system disorders in schizophrenia and suggest sexdependence of sensitivity of different brain structures to harmful prenatal stimulation.