Faculty of Health Sciences, Department of Developmental Molecular Genetics, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Neuropsychopharmacology. 2010 Apr;35(5):1138-54. doi: 10.1038/npp.2009.219. Epub 2009 Dec 30.
Neurodevelopmental disorders, such as schizophrenia and autism, have been associated with disturbances of the GABAergic system in the brain. We examined immediate and long-lasting influences of exposure to the GABA-potentiating drug vigabatrin (GVG) on the GABAergic system in the hippocampus and cerebral cortex, before and during the developmental switch in GABA function (postnatal days P1-7 and P4-14). GVG induced a transient elevation of GABA levels. A feedback response to GABA enhancement was evident by a short-term decrease in glutamate decarboxylase (GAD) 65 and 67 levels. However, the number of GAD65/67-immunoreactive (IR) cells was greater in 2-week-old GVG-treated mice. A long-term increase in GAD65 and GAD67 levels was dependent on brain region and treatment period. Vesicular GABA transporter was insensitive to GVG. The overall effect of GVG on the Cl(-) co-transporters NKCC1 and KCC2 was an enhancement of their synthesis, which was dependent on the treatment period and brain region studied. In addition, a short-term increase was followed by a long-term decrease in KCC2 oligomerization in the cell membrane of P4-14 hippocampi and cerebral cortices. Analysis of the Ca(2+) binding proteins expressed in subpopulations of GABAergic cells, parvalbumin and calbindin, showed region-specific effects of GVG during P4-14 on parvalbumin-IR cell density. Moreover, calbindin levels were elevated in GVG mice compared to controls during this period. Cumulatively, these results suggest a particular susceptibility of the hippocampus to GVG when exposed during days P4-14. In conclusion, our studies have identified modifications of key components in the inhibitory system during a critical developmental period. These findings provide novel insights into the deleterious consequences observed in children following prenatal and neonatal exposure to GABA-potentiating drugs.
神经发育障碍，如精神分裂症和自闭症，与大脑中的 GABA 能系统紊乱有关。我们研究了暴露于 GABA 增强药物 vigabatrin（GVG）对海马体和大脑皮层 GABA 能系统的即时和长期影响，在 GABA 功能发育转变期间（出生后第 1-7 天和第 4-14 天）前后。GVG 诱导 GABA 水平短暂升高。GABA 增强的反馈反应表现为谷氨酸脱羧酶（GAD）65 和 67 水平的短期下降。然而，在 2 周龄的 GVG 处理小鼠中，GAD65/67-免疫反应（IR）细胞的数量更多。GAD65 和 GAD67 水平的长期增加依赖于脑区和治疗期。囊泡 GABA 转运体对 GVG 不敏感。GVG 对 Cl(-)共转运体 NKCC1 和 KCC2 的整体影响是增强它们的合成，这取决于治疗期和研究的脑区。此外，在 P4-14 海马体和大脑皮层的细胞膜中，KCC2 寡聚体的短期增加后出现长期减少。对 GABA 能细胞亚群中表达的 Ca(2+)结合蛋白，即 parvalbumin 和 calbindin 的分析表明，GVG 在 P4-14 期间对 parvalbumin-IR 细胞密度具有特定的区域效应。此外，在这段时间内，GVG 小鼠的 calbindin 水平比对照组升高。总之，我们的研究表明，在 P4-14 期间暴露于 GVG 时，海马体特别容易受到影响。总之，我们的研究在关键发育期间确定了抑制系统中关键成分的修饰。这些发现为在儿童中观察到的产前和新生儿暴露于 GABA 增强药物的有害后果提供了新的见解。
