Functional roles of the glial glutamate transporter (GLAST) in emotional and cognitive abnormalities of mice after repeated phencyclidine administration

• Published in: European neuropsychopharmacology Vol. 29; no. 8; pp. 914 - 924
• Main Authors: Uchida, Mizuki, Hida, Hirotake, Mori, Kentaro, Yoshimi, Akira, Kitagaki, Shinji, Yamada, Kiyofumi, Hiraoka, Yuichi, Aida, Tomomi, Tanaka, Kohichi, Ozaki, Norio, Noda, Yukihiro
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2019
• Subjects: Glial glutamate and aspartate transporter; Phencyclidine; Schizophrenia; Schizophrenia; Glial glutamate and aspartate transporter; Phencyclidine
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2019.06.005

•Repeated PCP administration induces emotional and cognitive impairments.•Repeated PCP administration is associated with increase of GLAST and S100 in the PFC.•Decreased extracellular glutamate levels induced by overexpression of GLAST.•Behavioral abnormalities are not observed in PCP-administered GLAST+/− mice.•GLAST dysfunction plays important roles in the development of behavioral abnormalities.
Alterations of the glutamatergic system components, including N-methyl-d-aspartate (NMDA) receptors are relevant to the pathophysiology of schizophrenia. Repeated phencyclidine (PCP) administration induces several schizophrenia-like psychobehavioral abnormalities and decreases extracellular glutamate levels, which are associated with increased levels of glial glutamate and aspartate transporter (GLAST) in the prefrontal cortex (PFC) of mice. In the present study, we investigated the functional roles of GLAST in the emotional and cognitive abnormalities in mice following repeated PCP administration by using GLAST heterozygous (+/−) mice, since GLAST mutant mice are a useful tool for elucidating the contribution of glutamate dysfunction to the pathophysiology of schizophrenia. PCP-administered GLAST wild-type (+/+) mice showed enhancement of immobility in a forced swimming test, impairments of visual recognition memory in a novel object recognition test, decrease in high potassium (K+)-induced extracellular glutamate release, and overexpression of GLAST and S100 proteins in the PFC, compared to saline-administered GLAST+/+ mice. Such behavioral and neurochemical abnormalities were not observed in PCP-administered GLAST+/− mice. In conclusion, these results clearly suggest that genetic GLAST dysfunction and glial activation play important roles in the development of emotional and cognitive abnormalities in PCP-administered GLAST+/+ mice.