Research reportKetamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice

•Ketamine administration in mice on PND 7, 9 and 11.•Characterization of schizophrenia-like behavioral phenotype in adulthood.•Loss of parvalbumin immunoreactivity in the prefrontal cortex.•Severe persistent deficits in attentional tasks, social and novelty discrimination.

Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR-mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30 mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia.