Early developmental alterations in GABAergic protein expression in fragile X knockout mice

NEUROPHARMACOLOGY

卷:59

Article

Adusei, Daniel C.¹  Pacey, Laura K. K.¹  Chen, Duke¹  Hampson, David R.¹ 

[1] Univ Toronto, Dept Pharmaceut Sci, Leslie Dan Fac Pharm, Toronto, ON M5S 3M2, Canada

关键词: GABA(A);    GABA(B);    Autism;    GABA transaminase;    Glutamic acid decarboxylase;    Developmental expression;    Fragile X mental retardation protein;   

DOI  :  10.1016/j.neuropharm.2010.05.002

来源: Elsevier

【 摘 要 】

Fragile X syndrome is the most common heritable form of mental retardation. It is caused by silencing of the Fmr1 gene and the absence of the encoded protein. The purpose of this study was to examine global protein expression levels of GABA(A) and GABA(B) receptors, and GABAergic enzymes and trafficking proteins in fragile X knockout mice during brain maturation. Quantitative western blotting of homogenates of forebrain revealed that the levels of GABA(A) beta 1 and beta 3, GABA(B)-R1, NKCC1, KCC2, gephyrin and ubiquilin were not significantly different from wild-type mice at any of the postnatal time points examined. In contrast, the GABA(A) receptor alpha 1, beta 2, and delta subunits, and the GABA enzymes GABA transaminase and succinic semialdehyde dehydrogenase were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse brain. The GABA(A) receptor alpha 1 and beta 2 subunits displayed a divergent pattern of developmental expression whereby alpha 1 was reduced in the immature brain but regained a level of expression similar to wild-type mice by adulthood, while the expression of beta 2 was similar to wild-types at postnatal day 5 but reduced at day 12 and in the adult brain. The GABA(A) receptor delta subunit and the GABA catabolic enzymes GABA transaminase and succinic semialdehyde dehydrogenase were simultaneously but transiently decreased only at postnatal day 12. Our results demonstrate that GABA(A) receptor subunits and GABA enzymes display complex patterns of changes during brain development suggesting that dynamic interactions may occur between GABA transmitter levels and GABA receptors in fragile X syndrome. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

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