title: Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development.
abstract: Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment.
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. 13324568099@163.com.
authors: Lu
authors: L
authors: Wang
authors: Department of Gastroenterology and Endoscopy Center, No. 323 Hospital of PLA, Xi'an 710054, China. vivian_27998@sina.com.
authors: Yan
authors: Y
authors: Wang
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. zsmapril_417@163.com.
authors: Shimeng
authors: S
authors: Zhou
authors: Fifth Company, Second Battalion, Cadet Brigade, Fourth Military Medical University, Xi'an 710032, China. liukun_yang@126.com.
authors: Liukun
authors: L
authors: Yang
authors: Fifth Company, Second Battalion, Cadet Brigade, Fourth Military Medical University, Xi'an 710032, China. 1997sqx@sina.com.
authors: Qixin
authors: Q
authors: Shi
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. yujiao_li@126.com.
authors: Yujiao
authors: Y
authors: Li
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. kunzhang1900@163.com.
authors: Kun
authors: K
authors: Zhang
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. yanglefmmu@163.com.
authors: Le
authors: L
authors: Yang
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. minggao@fmmu.edu.cn.
authors: Minggao
authors: M
authors: Zhao
authors: Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China. yangqifmmu@126.com.
authors: Qi
authors: Q
authors: Yang
keywords: FMRP; GABA; astrocyte; fragile X syndrome; glutamate; oxidative stress