Neonatal Phencyclidine Treatment in Mice Induces Behavioral, Histological and Neurochemical Abnormalities in Adulthood

Abstract

N-Methyl-D-aspartate (NMDA)-type glutamic acid receptors play a critical role in excitatory synaptic transmission, synaptic plasticity and neuronal development in the central nervous system. During the developmental stage from week 25 of gestation to birth in humans, elongation and branching of axons and dendrites of nerve cells, synapse formation, myelination and realignment of nerve pathways (neural circuits) for acquiring higher neural function actively proceed, and this stage corresponds to postnatal weeks 1 through 2 in mice.1) It is generally recognized that non-synapse-mediated intercellular glutamic acid is largely involved in this process of nerve development. Stimulation of NMDA receptors facilitated radial migration of the cortical plate of excitatory nerve cells 2) and the selective blockade of NMDA receptors disturbed neuronal migration in the cerebral cortex.3)It has been reported that rats injected subcutaneously (s.c.) with phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, at 10 mg/kg once a day during the postnatal development stage (postnatal days 7, 9 and 11) exhibit an increase in spontaneous motor activity, impairment of prepulse inhibition and behavioral changes in respect of learning and cognition after attaining maturation.4-7) When rats neonatally administered PCP were examined for any changes in the binding capacity of NMDA receptors and g-aminobutyrate A (GABA A ) receptors at maturity by autoradiography using In the present study, we investigated brain function from the behavioral, anatomical and neurochemical viewpoints in mice injected with PCP at 10 mg/kg on postnatal days 7, 9 and 11. Especially, we focused on changes in social interaction in PCP-treated mice, and examined the effects of clozapine, an atypical antipsychotic drug, D-cycloserine, an NMDA receptor partial agonist, flumazenil, a benzodiazepine receptor antagonist, and SHC50911, a GABA B receptor antagonist on social interaction deficits in PCP-treated mice. Of note, as far as we are aware, this is the first experimental demonstration that neonatal PCP treatment in mice results in increased sensitivity to PCP, and impaired social interaction behaviors in adulthood, which are accompanied by a decrease in the number of GABAergic interneurons and spine density in the frontal cortex and hippocampus, and abnormal monoamine metabolism in the brain. Neonatal PCP treatment in mice could be regarded as a neurodevelopmental animal model for schizophrenia. MATERIALS AND METHODSMethods. Animals Male mice aged 13 weeks old and female mice aged 13 weeks old Crlj:CD1 (ICR) were mated, and male offspring were used on postnatal day 7. Animals were maintained in a room controlled at 23°C and 55% humidity with a 12-h lighting cycle (lights on: 6:00 a.m.), and 12 ventilations/h. Animals had free access to solid feed (CRF-1; Oriental Yeast Co., Ltd., Tokyo, Japan) from feed- Kakuma-machi, Kanazawa 920-1192, Japan: b Nihon Bioresearch Inc.; 6-104 Majima, Fukuju-cho, Hashima, Gifu 501-6251, Japan: c Narabyouri Research Co.,...

Impaired Fear Memory Specificity Associated with Deficient Endocannabinoid-Dependent Long-Term Plasticity

“…In addition, PCP-treated mice showed normal levels of uninduced locomotor activity in a novel environment Figure S1f), which is consistent with the previous study (Nakatani-Pawlak et al, 2009). Consistent with a previous report (Grayson et al, 2007;Nakatani-Pawlak et al, 2009;Wiley et al, 2003), PCPtreated mice exhibited abnormal behavior in the novel object recognition task (Supplementary Figures S3a and b) but normal performance in the object location task (Supplementary Figures S3c-f).…”

“…Consistent with a previous report (Grayson et al, 2007;Nakatani-Pawlak et al, 2009;Wiley et al, 2003), PCPtreated mice exhibited abnormal behavior in the novel object recognition task (Supplementary Figures S3a and b) but normal performance in the object location task (Supplementary Figures S3c-f). One difference between these two behavioral tasks is that novel object recognition memory test involves exposure to novelty (which may generate mild fear), while object location test relies entirely on familiar context and objects.…”

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

“…Early postnatal NMDAR blockade produces a decrease in the number of PV + -labeled neurons and principal neuron spine density in the frontal cortex, nucleus accumbens, and hippocampus in rodents when these are analyzed in adulthood (21,170,235). Direct confirmation of the role of NMDAR function during postnatal development in the expression of schizophrenia-like behaviors comes from results showing that genetic ablation of these receptors from PV + neurons decreases the expression of PV, produces disinhibition of pyramidal neurons, and leads to schizophrenia-related behaviors when mice reach adulthood (18,29,113).…”

“…Such effect could be detrimental for the transcriptional program that controls the maturation of the PV + neuronal system, leading to structural alterations of the cortical network. Accumulating evidence shows that embryonic and perinatal NMDAR antagonist exposures, contrary to the reversible effects observed in adults (15), can induce a loss of PV + neurons in several regions, and produce persistent behavioral and neurochemical deficits when animals reach adulthood (7,21,53,170,207,214,235,242). High doses of NMDA antagonists during the perinatal period were previously shown to lead to diminished numbers of PV-expressing neurons when animals reached adulthood.…”

Neonatal administration of phencyclidine decreases the number of putative inhibitory interneurons and increases neural excitability to auditory paired clicks in the hippocampal CA3 region of freely moving adult mice

“…This model exhibits abnormal behaviors after attaining maturation, similarly in patients with schizophrenia who usually develop symptoms after adolescence. In the neonatal PCP model, animals are repeatedly injected with PCP during the neonatal period (usually three times, on postnatal days 7, 9 and 11), and subsequent testing can be performed during adulthood (Wang et al, 2001(Wang et al, , 2003Andersen and Pouzet, 2004;Depoorte`re et al, 2005;Nakatani-Pawlak et al, 2009). After attaining maturation, animals that were neonatally injected with PCP exhibit deficits in working memory (Wang et al, 2001;Andersen and Pouzet, 2004;Nakatani-Pawlak et al, 2009), social interaction (Nakatani-Pawlak et al, 2009) and prepulse inhibition (Wang et al, 2001(Wang et al, , 2003, which correspond with the 0306-4522/12 $36.00 Ó 2012 IBRO.…”