Developmental disruption of serotonin transporter function impairs cerebral responses to whisker stimulation in mice.
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.
Esaki
Takanori
T
Laboratory of Cerebral Metabolism, National Institute of Mental Health, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Cook
Michelle
M
Shimoji
Kazuaki
K
Murphy
Dennis L
DL
Sokoloff
Louis
L
Holmes
Andrew
A
D000818:Animals; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D015398:Signal Transduction / Q000187:drug effects; D013003:Somatosensory Cortex / Q000187:drug effects / Q000502:physiology*; D020886:Somatosensory Disorders / Q000235:genetics / Q000503:physiopathology*; D014738:Vibrissae / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism*
D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; D005947:Glucose; D010134:Fenclonine