Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice
Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice
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DOI：
10.1073/pnas.0501509102
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发表时间：
2005-04-12
影响因子：
11.1
通讯作者：
Holmes, A
中科院分区：
文献类型：
--
作者：
Esaki, T;Cook, M;Holmes, A
越来越多的证据表明5-羟色胺（5-羟色胺，5-HT）对哺乳动物的大脑发育有重要影响。啮齿类动物出生后早期发育过程中5-羟色胺信号的遗传和药理学破坏会导致神经解剖学皮层异常，包括体感觉皮层畸形。5-羟色胺对发育的干扰可能造成的功能后果尚不清楚。我们研究了5-羟色胺转运体（5-HTT）基因缺失对小鼠感觉刺激的体感觉反应的影响。采用定量2-脱氧[C-14]葡萄糖法测定清醒成年小鼠单侧须刺激时局部脑葡萄糖利用率（1CMR(glc)）。5-HTT-/-小鼠在须-桶皮层通路的四个主要站点（三叉神经的脊髓和主要感觉核、丘脑腹侧后内侧核和体感觉皮层的桶区）的1CMR（glc）在刺激下增加，但明显低于5-HTT+/+对照组。在出生后第0天和第1天，通过给予选择性色氨酸羟化酶抑制剂对氯苯丙氨酸来降低大脑5-羟色胺水平，可以恢复成年5-羟色胺-/-小鼠的须到桶皮质通路功能激活的代谢反应。这些结果表明，5-HT -/-小鼠这一通路的功能缺陷可能是由于出生后5-HT活性过高。与5-HTT+/+对照组相比，有或没有产后对氯苯丙氨酸治疗的5-HTT-/-小鼠在须到桶皮层通路和整个大脑中表现出更低的静息（未刺激）1CMR（glc）。这些发现对理解5-羟色胺神经传递在出生后发育关键时期对大脑功能的遗传和药理学破坏的潜在长期影响具有重要意义。
There is growing evidence that serotonin (5-hydroxtryptamine, 5-HT) has major influences on brain development in mammals. Genetic and pharmacological disruption of 5-HT signaling during early postnatal development in rodents causes neuroanatomical cortical abnormalities, including malformations in the somatosensory cortex. Possible functional consequences of this developmental perturbation by 5-HT are not yet understood. We have examined the effects of deletion of the 5-HT transporter (5-HTT) gene on somatosensory responses to sensory stimulation in mice. Local cerebral glucose utilization (1CMR(glc)) was measured by the quantitative 2-deoxy[C-14]glucose method during unilateral whisker stimulation in awake adult mice. 1CMR(glc) was increased by stimulation but to a markedly lesser extent in 5-HTT-/- mice than in 5-HTT+/+ controls in each of four major stations in the whisker-to-barrel cortex pathway (the spinal and principal sensory trigeminal nuclei, the ventral posteromedial thalamic nucleus, and the barrel region of the somatosensory cortex). Lowering brain 5-HT levels by administration of the selective tryptophan hydroxylase inhibitor p-chlorophenylalanine on postnatal days 0 and 1 restored the metabolic responses to functional activation in the whisker-to-barrel cortex pathway in adult 5-HTT-/- mice. These results indicate that functional deficits in this pathway in 5-HTT-/- mice may be due to excessive postnatal 5-HT activity. With or without postnatal p-chlorophenylalanine treatment, 5-HTT-/- mice exhibited lower resting (unstimulated) 1CMR(glc) than did 5-HTT+/+ controls in the whisker-to-barrel cortex pathway and throughout the brain. These findings have implications for understanding the potential long-term consequences of genetic and pharmacological disruption of 5-HT neurotransmission on cerebral functions during critical periods of postnatal development.