Altered lipid peroxidation, perineuronal net and oligodendrocyte markers in the frontal cortex of a dual-hit neurodevelopmental model support its relevance to schizophrenia.

Introduction: The pathogenesis of schizophrenia begins in early neurodevelopment and leads to an array of frontal cortical deficits. They include redox dysregulation, white matter perturbation, loss of perineuronal nets (PNNs) and reduced synaptic density. It is therefore highly desirable that preclinical models used to understand disease, select drug targets and evaluate novel therapeutics encompass similar changes. One approach to improved preclinical modeling incorporates dual-hit neurodevelopmental interventions, like neonatal administration of phencyclidine (PCP, to disrupt development of glutamatergic circuitry) then post-weaning isolation (Iso, to mimic adolescent social stress). We recently showed that rats exposed to PCP-Iso develop GABAergic and inflammatory changes in the frontal cortex, and the current study expands on this by comparing changes to additional cellular and extracellular matrix markers relevant to oxidative stress, myelination, PNN integrity and synaptic vesicle density. Methods: The study used tissue from a previously described cohort of male Lister-hooded rats. They received saline vehicle (Veh, 1 ml/kg s.c.) or PCP (10 mg/kg s.c) on postnatal days (PND) 7, 9 and 11 then were housed in social groups (Gr, 3-4/cage) or post-weaning isolation from PND 21 onwards. Declarative memory was assessed in adulthood (PND 57-80) using a novel object discrimination (NOD) test. Frontal cortical samples were obtained on PND 79-80 and used for immunohistochemical or lectin binding examinations of the lipid peroxidation product 4-hydroxynonenal (4-HNE), oligodendrocyte-associated protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), PNNs and synaptic vesicle glycoprotein 2A (SV2A) throughout the orbitofrontal, prelimbic and infralimbic cortices. In each case data from dual-hit PCP-Iso and single-hit Veh-Iso were compared to each other, and to data from Veh-Gr controls. Results: Single-hit isolation-reared and dual-hit PCP-Iso both showed impaired declarative memory. They also both exhibited reduced PNN density in the orbitofrontal cortex and reduced PNN thickness in the prelimbic/infralimbic cortex. However, PCP-Iso showed additional PNN thinning, 4-HNE upregulation and CNPase downregulation in orbitofrontal regions. Discussion: These findings enhance the face validity of PCP-Iso and support wider use of this preclinical model for evaluating novel therapeutics designed to support parvalbumin-positive neurons and PNNs, promote myelination or normalize redox dysregulation. Unaltered SV2A expression in young adult PCP-Iso mirrors recent dorsolateral prefrontal cortical findings in first-episode psychosis, supports expectations that increased microglial activation precedes aberrant synaptic pruning, and justifies further examinations of synaptic markers in PCP-Iso at later developmental stages.