Developmental Disruption of Serotonin Transporter Function Impairs Cerebral Responses to Whisker Stimulation in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 15; pp. 5582 - 5587
• Main Authors: Esaki, Takanori, Cook, Michelle, Shimoji, Kazuaki, Murphy, Dennis L., Sokoloff, Louis, Holmes, Andrew
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.04.2005; National Acad Sciences
• Subjects: Animals; Behavioral neuroscience; Biological Sciences; Brain; Brain research; Developmental biology; Female; Fenclonine - pharmacology; Genotypes; Glucose - metabolism; Male; Mammals; Membrane Glycoproteins - deficiency; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Transport Proteins - deficiency; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Mice; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Pharmacology; Rodents; Serotonin - metabolism; Serotonin - pharmacology; Serotonin Plasma Membrane Transport Proteins; Serotonin receptors; Signal Transduction - drug effects; Somatosensory cortex; Somatosensory Cortex - drug effects; Somatosensory Cortex - physiology; Somatosensory Disorders - genetics; Somatosensory Disorders - physiopathology; Statistical significance; Vibrissae - drug effects; Vibrissae - innervation; Vibrissae - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0501509102

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. lCMRglcwas 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) lCMRglcthan 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.