Nuñez Joseph L, McCarthy Margaret M
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Dev Neurobiol. 2007 Dec;67(14):1879-90. doi: 10.1002/dneu.20567.
Gamma-aminobutyric acid (GABA) is as an excitatory neurotransmitter during brain development. Activation of GABA(A) receptors in neonatal rat hippocampus results in chloride efflux and membrane depolarization sufficient to open voltage sensitive calcium channels. As development progresses, there is a decline in the magnitude of calcium influx subsequent to GABA(A) receptor activation and the number of cells that respond to GABA with excitation. By the second postnatal week in the rat, GABA action in the hippocampus is predominantly inhibitory. The functional consequences and endogenous regulation of developmental GABA-mediated excitation remains under-explored. Hippocampal neurons in the newborn male and female rat respond to GABA(A) receptor activation with increased intracellular calcium and are susceptible to GABA-mediated damage -- both being indicative of the excitatory nature of GABA. In the present study we observed that by postnatal day 7, only males are susceptible to GABA(A) agonist-induced damage and respond to GABA(A) agonist administration with elevated levels of intracellular calcium in cultured hippocampal neurons. By postnatal day 14, GABA(A) agonist administration was without effect on intracellular calcium in both males and females. The age-related sex difference in the impact of GABA(A) receptor activation correlates with a sex difference in chloride co-transporter expression. Males have elevated protein levels of pNKCC1 on PN0 and PN7, with no sex difference by PN14. In contrast, females displayed elevated levels of KCC2 on PN7. This converging evidence infers that sex affects the duration of GABA(A) receptor-mediated excitation during normal hippocampal development, and provides a mechanism by which the effect is mediated.
γ-氨基丁酸（GABA）在大脑发育过程中作为一种兴奋性神经递质。新生大鼠海马体中GABA(A)受体的激活会导致氯离子外流和膜去极化，足以打开电压敏感钙通道。随着发育的进行，GABA(A)受体激活后钙内流的幅度以及对GABA产生兴奋反应的细胞数量都会下降。在大鼠出生后的第二周，海马体中GABA的作用主要是抑制性的。发育过程中GABA介导的兴奋的功能后果和内源性调节仍未得到充分探索。新生雄性和雌性大鼠的海马神经元对GABA(A)受体激活的反应是细胞内钙增加，并且易受GABA介导的损伤——这两者都表明了GABA的兴奋性本质。在本研究中，我们观察到在出生后第7天，只有雄性易受GABA(A)激动剂诱导的损伤，并且在培养的海马神经元中，对GABA(A)激动剂给药的反应是细胞内钙水平升高。到出生后第14天，GABA(A)激动剂给药对雄性和雌性的细胞内钙均无影响。GABA(A)受体激活影响的年龄相关性别差异与氯化物共转运体表达的性别差异相关。雄性在出生后第0天和第7天pNKCC1的蛋白水平升高，到出生后第14天没有性别差异。相反，雌性在出生后第7天KCC2水平升高。这些汇聚的证据推断，性别会影响正常海马发育过程中GABA(A)受体介导的兴奋持续时间，并提供了一种介导这种影响的机制。
