GABA homeostasis contributes to the developmental programming of anxiety-related behavior
GABA homeostasis contributes to the developmental programming of anxiety-related behavior
复制标题
DOI：
10.1016/j.brainres.2008.03.006
复制
发表时间：
2008-05-19
期刊：
影响因子：
2.9
通讯作者：
Gross, Cornelius
中科院分区：
文献类型：
--
作者：
Depino, Amaicha Mara;Tsetsenis, Theodoros;Gross, Cornelius
在发育过程中，当抑制性和兴奋性突触形成和完善时，稳态机制起作用以调节抑制性输入，从而将神经活动维持在正常范围内。随着大脑的成熟，突触发生减慢，并达到相对稳定的抑制水平。抑制性神经传递的缺陷与焦虑相关行为的增加有关，并且增强GABA功能（大脑中主要的抑制性神经递质）的药物是有效的抗焦虑药。这些观察结果提出了一种可能性，即在发育过程中神经回路活动的短暂扰动可能会引起抑制的补偿性变化，这种变化可能持续到成年期，并导致焦虑相关行为的变化。为了验证这一假设，我们在前脑突触发生的主要时期（P14-28）连续用GABA-A受体阳性调节剂地西泮治疗小鼠，并评估成年期的焦虑相关行为。对照实验证实了治疗一天后药物的抗焦虑作用和治疗两周后耐受性的发展。当在成年期进行测试时，在治疗结束后一个月，地西泮治疗的小鼠在旷场、高架十字迷宫和新物体行为范例中表现出显著增加的行为抑制。苯二氮卓类化合物结合位点在杏仁核和额叶皮质的水平，特别是在地西泮治疗的小鼠，证明GABA功能的稳态调整持续到成年。我们的研究结果表明，增加GABA能活性可以影响焦虑相关行为的发展规划。(C)2008 Elsevier B. V.保留所有权利。
During development, when inhibitory and excitatory synapses are formed and refined, homeostatic mechanisms act to adjust inhibitory input in order to maintain neural activity within a normal range. As the brain matures, synaptogenesis slows and a relatively stable level of inhibition is achieved. Deficits in inhibitory neurotransmission are associated with increased anxiety-related behavior and drugs that potentiate GABA function, the major inhibitory neurotransmitter in the brain, are effective anxiolytics. These observations raise the possibility that transient perturbations in the activity of neural circuits during development might induce compensatory changes in inhibition that could persist into adulthood and contribute to changes in anxiety-related behavior. To test this hypothesis, we treated mice continuously during the major period of forebrain synaptogenesis (P14-28) with the GABA-A receptor positive modulator diazepam and assessed anxiety-related behavior in adulthood. Control experiments confirmed anxiolytic effects of the drug following one day of treatment and the development of tolerance following two weeks of treatment. When tested in adulthood, one month after the end of treatment, diazepamtreated mice exhibited significantly increased behavioral inhibition in the open-field, elevated-plus maze, and novel object behavioral paradigms. Levels of benzodiazepine binding sites in amygdala and frontal cortex were specifically decreased in diazepamtreated mice demonstrating that homeostatic adjustments in GABA function persist into adulthood. Our results show that increased GABAergic activity can affect the developmental programming of anxiety-related behavior. (C) 2008 Elsevier B.V. All rights reserved.