The role of optogenetic stimulations of parvalbumin-positive interneurons in the prefrontal cortex and the ventral hippocampus on an acute MK-801 model of schizophrenia-like cognitive inflexibility

• Published in: Schizophrenia research 2023-02, Vol.252, p.198-205
• Main Authors: Patrono, Enrico, Hrůzova, Karolina, Svoboda, Jan, Stuchlík, Aleš
• Format: Article
• Language: English
• Subjects: Animals; Attentional set-shifting task; Cognition; Dizocilpine Maleate - pharmacology; Excitatory/inhibitory ratio; Gamma waves; Hippocampus - metabolism; Interneurons - metabolism; MK-801; Optogenetics; Parvalbumins - metabolism; Prefrontal Cortex - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; theta waves
• ISSN: 0920-9964; 1573-2509
• DOI: 10.1016/j.schres.2022.12.047

Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization. The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus. The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801. These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder.