Role Of Parvalbumin Interneurons In The Antidepressant And Psychosis-like Effects Of Ketamine

Objective:Recent clinical and animal studies have indicated that ketamine, a general anesthetic, possesses rapid and robust antidepressant effects, however, the underlying mechanisms are not totally understood. Meanwhile, some studies have demonstrated that ketamine can produce psychosis-like effects associated with decreased parvalbumin (PV) and glutamate decarboxylase67(GAD67) in PV containing interneurons, i.e. ketamine reduces the inhibitory function of parvalbumin (PV) interneurons, results in the disinhibition of glutamate (Glu) transmission, which subsequently increases the activation of pyramidal cells, and leads to the psychosis-like effects. Glu transmission is being enhanced when ketamine exerts antidepressant effects, therefore we hypothesize that the downregulation of PV interneurons is an important step involved in ketamine’s antidepressant effects. This study aims to investigate the effects of PV-positive interneurons in the antidepressant and psychosis-like effects of ketamine, and to differentiate the changes of PV interneurons, Glu, and gamma-aminobutyric acid (GABA) in the prefrontal cortex between ketamine’s antidepressant actions and psychosis-like effects.Methods:The forced swimming test (FST) was used to establish an acute rat model of depression, and ketamine was given for5consecutive days to set up a schizophrenia model in thie present study. The drugs of ketamine, apocynin (a nicotinamide adenine dinucleotide phosphate oxidase inhibitor, Nox2, which is reported to prevent ketamine-induced reduction in PV and GAD67levels in the brain) and GABA were applied in the present experimental procedure. Immobility time, locomotor activities and the scores of stereotyped behavior were recorded to detect the behavior changes in rats. Double lable immunofluorescent staining was employed to evaluate the expression of PV and GAD67and biochemical test and ELISA were used to determine the levels of Glu and GABA of prefrontal cortex immediately after behavior test.Results:Compared with saline administration, the immobility time decreased, the expression of PV and GAD67reduced, the Glu level increased and the GABA level decreased in the prefrontal cortex at0.5h after ketamine10mg/kg administration on rats (P<0.05). The immobility time remained decreased (P<0.05), however, the reduction of biochemistry values disappeared at2h after ketamine administration (P>0.05). Moreover, apocynin and GABA pretreatment blocked ketamine-induced antidepressant effects(P<0.05), and both apocynin and GABA did not elicit any significant change in the immobility time. The scores of locomotor and stereotyped behaviors increased, the expression of PV and GAD67reduced, the Glu level increased and the GABA level decreased in the prefrontal cortex of rats at0.5h after the last ketamine30mg/kg administration in the schizophrenia model (P<0.05). The change of behavior had no significant difference (P>0.05), however, the reduction of biochemistry values continued at2h after the last administration (P<0.05). At0.5h after the last ketamine30mg/kg administration, the Glu level in the prefrontal cortex of rats was higher than the level after the ketamine10mg/kg single administration (P <0.05). Nevertheless, there was no significant difference in the GABA level and the expression of PV and GAD67(P>0.05). At2h after the last ketamine30mg/kg administration, the Glu level was higher, the GABA level was lower, and the expression of PV and GAD67was lower than those after the ketamine10mg/kg single administration (P<0.05).Conclusions:The downregulation of PV-positive interneurons in the prefrontal cortex are associated with the antidepressant actions and propsychotic effects of ketamine, which may be partially mediated by the disinhibition of Glu neurotransmission. The degree and persistence time of PV interneurons downregulation and disinhibition of Glu transmission are different between the antidepressant actions and the propsychotic effects of ketamine.