Transcription profiling by array of CIC-2 knock out mice

ClC-2 is a broadly expressed Cl- channel of the CLC family of Cl- channels and transporters which is abundantly expressed in brain. Here it was proposed to participate in lowering the cytoplasmic Cl- concentration of neurons, a process that establishes an inhibitory response to the neurotransmitters GABA and glycine (Staley et al., 1996). Heterozygous mutations in CLCN2 (the gene encoding ClC-2) were recently reported in a few patients with three clinically distinct forms of epilepsy (Haug et al, 2003). However, the disruption of ClC-2 in mice (ClC-2 KO mouse) did not entail epilepsy (Bosl et al., 2001; Nehrke et al., 2002) but myelin vacuolation in fiber tracts of the central nervous system. We used a gene expression profiling of the ClC-2 KO mouse in brain to identify possible disease mechanism which cause the observed myelin phenotype. As these myelin vacuolation became apparent in the fiber tracts of ClC-2 KO cerebellum at P28 and increased with age, we analysed the cerebellum of ClC-2 KO mice at different postnatal ages, before (P14) and after (P35) the KO cerebellum has been affected by myelin vacuolation.ClC-2属于氯离子通道（Cl- channel）与转运蛋白CLC家族，是一类广泛分布的氯离子通道，在大脑中呈高丰度表达。该蛋白被认为参与降低神经元胞质内氯离子浓度，这一过程是介导神经递质γ-氨基丁酸（GABA）与甘氨酸（glycine）产生抑制性应答的关键基础（Staley等，1996）。近期研究在少数患有三种临床表型各异的癫痫患者中，发现了CLCN2（编码ClC-2的基因）的杂合突变（Haug等，2003）。然而，小鼠体内ClC-2基因敲除（Knock Out, KO）后并未引发癫痫表型（Bosl等，2001；Nehrke等，2002），反而会导致中枢神经系统纤维束出现髓鞘空泡变性。本研究通过对大脑组织中ClC-2基因敲除小鼠开展基因表达谱分析，旨在明确引发上述髓鞘病变表型的潜在致病机制。鉴于该髓鞘空泡变性在出生后第28天（P28）的ClC-2基因敲除小鼠小脑纤维束中即可观测到，并随年龄增长逐渐加重，因此我们对不同出生后发育阶段的ClC-2基因敲除小鼠小脑进行了分析，涵盖病变发生前（出生后第14天，P14）与病变发生后（出生后第35天，P35）两个关键时期。