Sub-chronic administration of phencyclidine induces a transient pro-inflammatory CNS response in a mouse model for schizophrenia

Cognitive Impairments Associated with Schizophrenia (CIAS) can be induced in rodents via sub-chronic administration of phencyclidine (the scPCP model), however, the mechanisms underlying the onset of deficits is not well understood. Inflammation is implicated in the induction and maintenance of CIAS in patients (Upthegrove et al., 2014) as well as damage to parvalbumin-positive interneurons (PVIs), which are essential for normal cognition. Similar inflammatory changes (Yu et al., 2023) and reduced PV expression (Gigg et al., 2020) are observed following scPCP dosing, however, the evolution of these changes during the PCP-washout period have not been probed. The current study measured PV, IL-6, IL-1β, IL-23 and TNFα within the prefrontal cortex (PFC) and dorsal hippocampus (dH) at early post-dosing timepoints to investigate the mechanisms underlying the induction of CIAS in scPCP mice. <br/>32 adult female C57BL/6J mice were divided into scPCP and scVehicle groups and dosed daily (s.c.) for 10 days with 10mg/kg PCP or 0.9% saline. PFC and dH samples were collected 24h and 2 weeks after the final PCP dose, with half of each treatment group sacrificed at each timepoint. Bead-based immunoassay and chemiluminescent Western analysis were used. Pro-inflammatory composite scores were calculated by averaging the Z-scores for IL-6, TNFα, IL-1β and IL-23 (Z-score = (individual value – mean value)/standard deviation). Two-way ANOVA compared composite scores and PV expression at each timepoint. <br/>Pro-inflammatory composite scores were significantly raised in mice at 24h (p&lt;0.01), but not two weeks (p=0.738) after scPCP treatment. PV expression was not affected by treatment at either the 24h (p=0.313) or two-week (p=0.084) timepoints. <br/>These data describe a scPCP-induced pro-inflammatory response 24h, but not two weeks, after PCP dosing cessation, implicating these cytokines in the induction of CIAS in the scPCP model, but not in the maintenance of these deficits. Changes to PV levels were not observed at either timepoint, despite earlier work identifying a reduction in PV in the dH of scPCP mice 15 weeks post-dosing (Gigg et al. 2020). These divergent findings indicate that PV deficits may take longer than two weeks to occur. <br/><br/>Gigg J et al.(2020) Synaptic biomarker reduction and impaired cognition in the sub-chronic PCP mouse model for schizophrenia. Journal of Psychopharmacology. 34(1):115-124.<br/>Upthegrove R et al.(2014) Cytokine function in medication-naïve first episode psychosis: A systematic review and meta-analysis. Schizophrenia Research. 155(1-3):101-108.<br/>Yu X et al.(2022) Fingolimod ameliorates schizophrenia-like cognitive impairments induced by phencyclidine in male rats. British Journal of Pharmacology. 18(2):161-173.<br/>