Behavioural Brain Research 220 (2011) 132–139 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Prenatal exposure to PCP produces behavioral deficits accompanied by the overexpression of GLAST in the prefrontal cortex of postpubertal mice Lingling Lu a,b , Takayoshi Mamiya a , Ping Lu a,b , Kazuya Toriumi a , Akihiro Mouri a,c , Masayuki Hiramatsu a , Li-Bo Zou b , Toshitaka Nabeshima a,d,∗ a Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan b Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China c Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan d Japanese Drug Organization for Appropriate Use and Research, Nagoya 468-0069, Japan article info Article history: Received 12 November 2010 Received in revised form 13 January 2011 Accepted 19 January 2011 Keywords: Prenatal PCP Behavior GLAST Glutamate transmission Prefrontal cortex Mice abstract Altered glutamatergic neurotransmission in the prefrontal cortex (PFC) has been implicated in a myriad of neuropsychiatric disorders. We previously reported that prenatal exposure to PCP produced long- lasting behavioral deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors. In addition, these behavioral changes were attenuated by clozapine treatment. However, whether the prenatal exposure adversely affects pre-synaptic glutamatergic neurotransmission in postpubertal mice remains unknown. In the present study, we investigated the involvement of prefrontal glutamatergic neurotransmission in the impairment of cognitive and emotional behavior after prenatal PCP treatment (5 mg/kg/day) from E6 to E18 in mice. The PCP-treated mice showed an impairment of recognition mem- ory in a novel object recognition test and enhancement of immobility in a forced swimming test at 8 weeks of age. Moreover, the prenatal treatment reduced the extracellular glutamate level, but increased the expression of a glial glutamate transporter (GLAST) in the PFC. The microinjection of DL-threo- -benzyloxyaspartate (DL-TBOA, 10 nmol/site/bilaterally), a potent blocker of glutamate transporters, reversed these behavioral deficits by enhancing the prefrontal glutamatergic neurotransmission. Taken together, prenatal exposure to PCP produced impairments of long-term memory and emotional function which are associated with abnormalities of pre-synaptic glutamate transmission in the PFC of postpuber- tal mice. These findings suggest the prenatal inhibition of NMDA receptor function to contribute partly to the pathophysiology of neurodevelopment-related disorders, such as schizophrenia. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Disruption of the brain’s development at an early stage can potentially alter neural networks and may increase the risk for neuropsychiatric disorders in later life. According to the neurodevelopmental hypothesis, disruption of the developing brain predisposes the neural systems to long-lasting structural and functional abnormalities, leading to the emergence of psy- chopathological behavior in adulthood [3]. NMDA receptor plays a critical role in neuronal development [10]. The stimulation of NMDA receptors during development is critical for the survival, differentiation and migration of immature ∗ Corresponding author at: Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, 150 Yagotoyama, Tenpaku-ku, Nagoya 468-8503, Japan. Tel.: +81 52 839 2735; fax: +81 52 839 2738. E-mail addresses: tnabeshi@meijo-u.ac.jp, tnabeshi@ccmfs.meijo-u.ac (T. Nabeshima). neurons [4,20], controls structure and plasticity [40], and estab- lishes normal neural networks in the developing brain [12]. On the other hand, pharmacological inhibition of NMDA receptors at an early stage disturbs neural function in development [6,13,22]. The blockade of NMDA receptors with phencyclidine (PCP), a noncompetitive antagonist, produces a transient state of psychosis and schizophrenia-like deficits in normal subjects and exacerbates several symptoms in schizophrenia patients [18]. Moreover, PCP elicited a prolonged recrudescence of the acute psychotic state in patients with stable chronic schizophrenia, suggesting that a sim- ilar mechanism is compromised [21]. These observations, along with the finding of reduced glutamate levels in the cerebrospinal fluid of schizophrenic patients [19], form the basis of the gluta- matergic hypofunction hypothesis of schizophrenia. According to this hypothesis, PCP is widely used to pro- duce abnormal behavior and biochemical changes resembling the positive symptoms, negative symptoms, and cognitive deficits of patients with schizophrenia [32,33,38]. Although a series of schizophrenia-like symptoms are observed in PCP-treated adult 0166-4328/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2011.01.035