Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Abstract

Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70–120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

Deletion of the mitochondrial matrix protein cyclophilin-D prevents parvalbumin interneuron dysfunction and cognitive deficits in a mouse model of NMDA hypofunction

“…6G) on social interaction. Consistent with our previous reports (Jeevakumar et al, 2015; Phensy et al, 2017b), WT-KET mice showed reduced investigation times across trials 1, 2, and 5. In contrast, Ppif -/- -KET mice demonstrated investigation times similar to saline-treated controls across all five exposures, suggesting normal social interaction and recognition memory.…”

“…These tasks included a rule-shifting task to measure cognitive flexibility, a novel object recognition task which measures (short-term) memory for objects, and a social interaction task which tests deficits in social interaction and novelty discrimination (Fig. 6) (Jeevakumar et al, 2015; Phensy et al, 2017b).…”

“…Deficits in social cognition and interaction greatly impact the quality of life of patients with schizophrenia. KET-treated mice show reduced social interactions (Jeevakumar et al, 2015; Phensy et al, 2017b). To test if genetic deletion of CypD can prevent this social deficit, we performed a social interaction and recognition task (Fig.…”

“…Performance on the task relies heavily on interactions between PFC and hippocampal circuits (Korotkova et al, 2010), which are disrupted by blockade (Jadi et al, 2016) or ablation (Korotkova et al, 2010) of NMDARs. Both acute (Rajagopal et al, 2014) and developmental (Jeevakumar et al, 2015; Phensy et al, 2017b) KET-treatment results in reduced novel object recognition. Finally, we examined changes in social interaction in KET-treated WT and Ppif -/- animals.…”

“…Procedures for our rule-shifting task followed those previously described (Phensy et al, 2017b). Mice were food restricted to 85% of their free-feeding weight over two weeks and handled for at least 5 minutes a day.…”