ACTIVATION OF PREFRONTAL PARVALBUMIN INTERNEURONS AMELIORATES WORKING MEMORY DEFICIT EVEN UNDER CLINICALLY COMPARABLE ANTIPSYCHOTIC TREATMENT IN A MOUSE MODEL OF SCHIZOPHRENIA

Abstract Background One of the critical unmet medical needs in schizophrenia is to develop drugs that can improve cognitive deficits in schizophrenia. Several meta-analyses suggest that the existing cognitive enhancers, targeting specific receptor system, are minimal or no effect. Identifying neurobiological targets to improve cognitive deficits in schizophrenia is an attractive target for drug development. However, our understanding of the neural circuit mechanisms of them remains quite limited. In addition, previous studies utilizing animal models of schizophrenia have not fully considered the fact that patients with schizophrenia generally cannot discontinue antipsychotic medication due to the high risk of relapse. Previously, we demonstrated that the prelimbic cortex (PL) of the medial prefrontal cortex (mPFC), especially layer 2–3, is a candidate brain region responsible for working memory deficit in chronic phencyclidine (PCP) mouse model of schizophrenia. Aim & Objectives We aimed to understand the neural mechanisms underlying cognitive deficits specific to schizophrenia and identify therapeutic target. Method We performed multi-dimensional experiments, including histological analysis of the 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 PCP mouse model of schizophrenia. Results Chronic PCP administration led to alterations in excitatory and inhibitory synapses of layer 2–3 in the prelimbic cortex (PL), specifically in dendritic spines of pyramidal neurons, vesicular glutamate transporter 1 (VGLUT1) positive terminals, and parvalbumin (PV) positive GABAergic interneurons. 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 using hM3D(Gq)-DREADD and its selective ligand descloroclozapine, as confirmed by in vivo calcium imaging, ameliorated working memory deficit in this model even under clinically comparable olanzapine treatment which by itself inhibited PCP-induced psychomotor hyperactivity. Discussion & Conclusion These results show that selective activation of PV interneurons, which plays a pivotal role in the generation of gamma oscillation, in the PL improves working memory deficit in a PCP mouse model, even under clinically comparable olanzapine treatment. Our study provides information on promising translational approaches to facilitate novel drug discovery that improve cognitive deficits in schizophrenic patients taking antipsychotic medications.