Transitory glutathione deficit during brain development induces cognitive impairment in juvenile and adult rats: Relevance to schizophrenia

Abstract

Glutathione (GSH) metabolism dysfunction is one risk factor in schizophrenia. A transitory brain GSH deficit was induced in Wistar (WIS) and mutant (ODS; lacking ascorbic acid synthesis) rats using BSO (l-buthionine-(S,R)-sulfoximine) from post-natal days 5–16. When GSH was re-established to physiological levels, juvenile BSO-ODS rats were impaired in the water maze task. Long after treatment cessation, adult BSO-WIS/-ODS rats showed impaired place discrimination in the homing board with distributed visual or olfactory cues. Their accuracy was restored when a single cue marked the trained position. Similarly, more working memory errors were made by adult BSO-WIS in the radial maze when several olfactory cues were present. These results reveal that BSO rats did not suffer simple sensory impairment. They were selectively impaired in spatial memory when the task required the integration of multimodal or olfactory cues. These results, in part, resemble some of the reported olfactory discrimination and cognitive impairment in schizophrenia.

Introduction

Impairments in certain cognitive functions mediated by the prefrontal cortex and hippocampus have been implicated in schizophrenia. Convergent findings indicate that the cognitive disturbances are associated with alterations in the prefrontal circuitries (Lewis and Moghaddam, 2006) occurring during early development (Andreasen, 2000). Thus, schizophrenia is thought to arise from altered neurodevelopmental processes because of the interaction between genetic susceptibility and environmental risk factors. New evidence suggests that glutathione (GSH) deficit is one vulnerability factor in the pathophysiology of schizophrenia. As a main cellular non-protein antioxidant and redox regulator (Meister and Anderson, 1983), GSH protects nervous tissue against oxidative stress (Halliwell, 1992) and modulates redox-sensitive sites including N-methyl-d-aspartate (NMDA) receptors (Choi and Lipton, 2000, Kohr et al., 1994). Oxidative stress (Mahadik and Mukherjee, 1996, Prabakaran et al., 2004) and NMDA receptor malfunction (Coyle and Tsai, 2004, Olney et al., 1999) are proposed to be involved in psychiatric disease pathophysiology. Interestingly, GSH level was found low in the cerebrospinal fluid, medial prefrontal cortex (Do et al., 1995, Do et al., 2000) and post-mortem striatal tissue (Yao et al., 2006) of schizophrenic patients. The gene of the key GSH synthesizing enzyme glutamate cysteine ligase (GCL) modifier subunit (GCLM) was also recently found to be strongly associated with schizophrenia in two-case controls and one family study. GCLM gene expression was also decreased in patients’ fibroblasts (Tosic et al., 2006). Moreover, we observed lower GCL activity in patients’ fibroblasts exposed to an oxidative stress (Gysin et al., 2005, Do et al., 2006). Although a GSH problem is present in other neurodegenerative disease, these results support a dysregulated GSH metabolism in schizophrenia.

Establishing a reliable animal behavior that targets specific cognitive function remains a challenge. A complex question is how to assess impairments in multimodal integration; and how to relate deficits in neural processing to alterations of cognitive performance in rats? One way is to compare the cognitive impairments observed in patients with those induced in specific animal models. Thus, behavioral paradigms need to address learning, discrimination and working memory strategies, most of which seemed affected in schizophrenia. Beside cognitive deficits, impaired olfactory identification and discrimination seem prominent in schizophrenia (Malaspina et al., 2002, Corcoran et al., 2005). On this basis, we designed learning and discrimination tasks aimed at assessing spatial working memory performance in absence (water maze) or in presence (homing board, radial maze) of controlled olfactory cues.

Here, we characterized the behavioral effects of transitory GSH deficit in non-mutant Wistar and mutant Osteogenic Disorder Shionogi (ODS) rats. ODS rats were chosen because like humans, this strain is incapable of synthesizing ascorbic acid (Nishikimi and Yagi, 1996), an antioxidant able to compensate for the GSH decrease in normal rats (Martensson and Meister, 1992, Castagné et al., 2004a). The aim of the study was to examine the cognitive strategies of the BSO-treated animals 10 days following treatment cessation (when cerebral GSH is re-established to normal physiological level) and later in fully adult animal, to investigate possible worsening of cognitive capacities.