title: Ketamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice.
abstract: 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 (30mg/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.
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Jeevakumar
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Driskill
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Alyssa
authors.initials: A
authors.lastname: Paine
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Millad
authors.initials: M
authors.lastname: Sobhanian
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Haris
authors.initials: H
authors.lastname: Vakil
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Morris
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Ramos
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA. Electronic address: kroener@utdallas.edu.
authors.forename: Sven
authors.initials: S
authors.lastname: Kroener
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001526:Behavioral Symptoms / Q000139:chemically induced / Q000523:psychology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010320:Parvalbumins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Ketamine; NMDAR; Parvalbumin; Perinatal; Prefrontal cortex; Schizophrenia