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.
Highlights
Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and is caused by a mutation in the fragile X mental retardation gene (Fmr1) [1]
We report that increased glutamate and reduced glutamate and γ-aminobutyric acid (GABA) levels were neurotoxic to neuronal dendritic development
Density may underliecultures the aberrant morphology caused by KO astrocyte-conditioned medium (ACM), we staining prepared with the ACM, weneuronal prepared low‐density to neuronal visualize individual neurons using low-density cultures to visualize individual neurons using staining with the dendritic marker, MAP2 dendritic (Figure marker, MAP2 (Figure 1A)
Summary
Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and is caused by a mutation in the fragile X mental retardation gene (Fmr1) [1]. Mounting evidence is steadily implicating a role that astrocytes play in neuronal dendritic development [11,12]. The role of neurotoxic molecules released from Fmr KO astrocytes following neuronal damage remains unclear. Studies report that drugs used to treat excessive glutamate and insufficient γ-aminobutyric acid (GABA), signaling pathways affected by FMRP, are under different stages of development in FXS [15]. It is interesting to know whether the imbalance between excitatory and inhibitory circuitry is caused by a lack of astrocytic FMRP. We report that increased glutamate and reduced GABA levels were neurotoxic to neuronal dendritic development. The neurotoxicity resulted from an imbalance between the glutamate and GABA circuits in the brain, which contributes to oxidative stress in FXS. Our findings in this study suggest a new potential strategy for FXS treatment
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