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

doi:10.1073/pnas.0501509102

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

Laboratories of ^*Cerebral Metabolism and ^‡Clinical Science, National Institute of Mental Health, ^¶Section on Behavioral Science and Genetics, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, and ^†Positron Emission Tomography Department, Clinical Center, National Institutes of Health, Bethesda, MD 20892

Contributed by Louis Sokoloff, March 8, 2005

Abstract

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[¹⁴C]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.

Footnotes

↵ § To whom correspondence should be addressed at: Laboratory of Cerebral Metabolism, National Institute of Mental Health, Building No. 36, 1A-07, 36 Convent Drive, MSC 4030, Bethesda, MD 20892-4030. E-mail: louissokoloff{at}mail.nih.gov.
Abbreviations: 5-HT, 5-hydroxtryptamine (serotonin); 5-HTT, serotonin transporter; 5-HT1BR, 5-HT1B receptor subtype; lCMRglc, local cerebral glucose utilization; MAOA, monoamine oxidase A; PCPA, p-chlorophenylalanine; Pn, postnatal day n.