Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development.
Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development.
复制标题
DOI：
10.1186/1471-213x-8-112
复制
发表时间：
2008-11-28
影响因子：
--
通讯作者：
Gibson, K. Michael
中科院分区：
文献类型：
--
作者：
Jansen, Erwin E. W.;Struys, Eduard;Jakobs, Cornelis;Hager, Elizabeth;Snead, Carter;Gibson, K. Michael
SSADH（乙醛脱氢酶5a 1（Aldh 5a 1）; γ-羟丁酸（GHB）酸尿症）缺乏是GABA降解的缺陷，其中神经调节剂GABA和GHB积累。人类的表型是非进行性脑病，具有明显的双侧苍白球变色和可变癫痫发作，后者在Aldh 5a 1-/-小鼠中表现突出，伴有致死性惊厥。对小鼠神经组织的代谢研究表明，出生时GABA [及其衍生物琥珀酸半醛（SSA）、高肌肽（HC）、4，5-二羟基己酸（DHHA）和胍基丁酸（GB）]和GHB [及其类似物D-2-羟基戊二酸（D-2-HG）]升高。由于早期发作的癫痫发作和患者中观察到的神经结构异常，我们研究了Aldh 5a 1-/-胚胎发育过程中的代谢产物特征。从在E（胚胎出生日）10-13、14-15、16-17、18-19处死的妊娠母鼠和新生小鼠中获得胚胎。提取完整胚胎，并通过同位素稀释质谱法对每个胎龄组的代谢物进行定量（n = 5-15例受试者，Aldh 5a 1 +/+和Aldh 5a 1-/-）。使用t检验和单因素ANOVA与Tukey事后分析评价数据。显著性设定为第95百分位数。GABA和DHHA在Aldh 5a 1-/-小鼠的所有胎龄均显著升高，而GB仅在妊娠后期升高; SSA在任何时间点均未升高。GHB和D-2-HG随胎龄增加呈近似线性增加。在SSADH缺陷妊娠（n = 5）的人羊水中的相关研究也显示GABA显著增加。我们的研究结果表明Aldh 5a 1-/-小鼠的早期GABA能改变，可能被其他代谢物加剧，这可能会诱导兴奋状态升高，可能使这些动物的神经网络易患癫痫。
SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development. Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1+/+ and Aldh5a1-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile. GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA. Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.