Activation of prefrontal parvalbumin interneurons ameliorates working memory deficit even under clinically comparable antipsychotic treatment in a mouse model of schizophrenia

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2024-03, Vol.49 (4), p.720-730
• Main Authors: Arime, Yosefu, Saitoh, Yoshito, Ishikawa, Mikiko, Kamiyoshihara, Chikako, Uchida, Yasuo, Fujii, Kazuki, Takao, Keizo, Akiyama, Kazufumi, Ohkawa, Noriaki
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antipsychotic Agents - therapeutic use; Antipsychotics; Calcium; Calcium imaging; Chromatography, Liquid; Cognitive ability; Dendritic spines; Disease Models, Animal; Dopamine; Dopamine D2 receptors; Glutamic acid transporter; Humans; Hyperactivity; Interneurons; Interneurons - metabolism; Memory; Memory Disorders - drug therapy; Mental disorders; Mice; Neostriatum; Neuroimaging; Olanzapine; Olanzapine - adverse effects; Parvalbumin; Parvalbumins - metabolism; Phencyclidine; Phencyclidine - pharmacology; Prefrontal Cortex - metabolism; Psychotropic drugs; Pyramidal cells; Receptors, Dopamine D2; Schizophrenia; Schizophrenia - chemically induced; Schizophrenia - drug therapy; Schizophrenia - pathology; Short term memory; Synapses; Tandem Mass Spectrometry; γ-Aminobutyric acid
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-023-01769-z

One of the critical unmet medical needs in schizophrenia is the treatment for cognitive deficits. However, the neural circuit mechanisms of them remain unresolved. Previous studies utilizing animal models of schizophrenia did not consider the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Here, we used multi-dimensional approaches, including histological analysis of the prelimbic cortex (PL), LC-MS/MS-based in vivo dopamine D2 receptor occupancy analysis for antipsychotics, in vivo calcium imaging, and behavioral analyses of mice using chemogenetics to investigate neural mechanisms and potential therapeutic strategies for working memory deficit in a chronic phencyclidine (PCP) mouse model of schizophrenia. Chronic PCP administration led to alterations in excitatory and inhibitory synapses, specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons located in layer 2-3 of the PL. Continuous administration of olanzapine, which achieved a sustained therapeutic window of dopamine D2 receptor occupancy (60-80%) in the striatum, did not ameliorate these synaptic abnormalities and working memory deficit in the chronic PCP-treated mice. We demonstrated that chemogenetic activation of PV neurons in the PL, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited only PCP-induced psychomotor hyperactivity. Our study suggests that targeting prefrontal PV neurons could be a promising therapeutic intervention for cognitive deficits in schizophrenia in combination with antipsychotic medication.