The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK801 model of schizophrenia-like cognitive inflexibility

Abstract

Background and HypothesisSchizophrenia research arose in the last decades, focusing more on its neural basis. Executive functions such as decision making and cognitive flexibility are the main cognitive areas that are impaired and are considered schizophrenia endophenotypes. Recently, cognitive impairment has been connected with the ablation of glutamatergic NMDARs resulting in increased cortical activity. Selective NMDARs antagonists such as dizocilpine have been used to model cognitive inflexibility in schizophrenia. Moreover, a decreased GABAergic inhibitory activity has been shown elsewhere along with the enhanced cortical activity. This NMDARs/GABA unbalanced ratio may reduce the entrainment of prefrontal gamma and hippocampal theta rhythm, resulting in a prefrontal-hippocampal gamma/theta band desynchronization. Study DesignThe study addressed the role of acute administrations of dizocilpine to model schizophrenia-like cognitive inflexibility in rats. We used a new version of the attentional set-shifting task, where rats learned switching/reversing the relevant rule. Moreover, we used the new ASST after dizocilpine systemic injections to test cognitive flexibility. Finally, we used in vivo optogenetic stimulations at specific light pulses of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus. ResultsThe first experiments showed that acute dizocilpine in rats reproduced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that appropriate optogenetic light pulses frequencies could rescue the cognitive flexibility previously altered by acute dizocilpine. ConclusionsThese findings advance our knowledge on the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may serve as a standpoint for further research of this severe psychiatric disorder.