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

AUTOR(ES)

Esaki, Takanori

FONTE

National Academy of Sciences

RESUMO

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