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Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5582-7. Epub 2005 Apr 4.

Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice.

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Laboratory of Cerebral Metabolism, National Institute of Mental Health, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.


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 (lCMR(glc)) was measured by the quantitative 2-deoxy[(14)C]glucose method during unilateral whisker stimulation in awake adult mice. lCMR(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) lCMR(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.

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