J Neuropathol Exp Neurol. 2005 Nov;64(11):1018-1027
Serotonin Transporter Abnormality in the Dorsal Motor Nucleus of the Vagus in Rett Syndrome: Potential Implications for Clinical Autonomic Dysfunction
Paterson DS, Thompson EG, Belliveau RA, Antalffy BA, Trachtenberg FL, Armstrong DD, Kinney HC.
From the Department of Pathology (DSP, EGT, RAB, HCK), Children's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology (BAA, DDA), Texas Children's Hospital and Baylor College of Medicine, Houston, Texas; and New England Research Institutes (FLT), Watertown, Massachusetts.Abstract
Autonomic dysfunction is prevalent in girls with Rett syndrome, an X-chromosome-linked disorder of mental retardation resulting from mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). This gene plays a role in regulating neuronal activity-dependent gene expression, including brain-derived neurotrophic factor (BDNF), which is a potent serotonergic (5-HT) neuronal growth factor. We analyzed selected parameters of the 5-HT system of the medulla in autopsied patients with Rett syndrome because of the role of BDNF in 5-HT cell development and because 5-HT plays a key role in modulating autonomic control. 5-HT neurons were identified by immunostaining for tryptophan hydroxylase, the biosynthetic enzyme for 5-HT. We quantitated the number of 5-HT cells in the medulla at 2 standardized levels in 11 Rett and 7 control cases. There was no significant difference in 5-HT cell number between the groups. We analyzed binding to the serotonin transporter (SERT) using the radioligand [I]-RTI-55 with tissue autoradiography in 7 Rett and 5 controls in 9 cardiorespiratory-related nuclei. In the dorsal motor nucleus of the vagus (DMX) (preganglionic parasympathetic outflow), SERT binding for the control cases decreased significantly over time (p = 0.049) but did not change in the Rett cases (p = 0.513). Adjusting for age, binding between the Rett and control cases differed significantly in this nucleus (p = 0.022). There was a marginally significant age versus diagnosis interaction (p = 0.06). Thus, altered 5-HT innervation and/or uptake in the DMX may contribute to abnormal 5-HT modulation of this major autonomic nucleus in patients with Rett syndrome. These data suggest hypotheses concerning 5-HT modulation of vagal function for testing in MeCP2 knockout mice to understand mechanisms underlying autonomic dysfunction in patients with Rett syndrome.Lay Summary
The autonomic (or "involuntary") nervous system controls bodily functions that are not under conscious control. Various autonomic abnormalities have been reported in RTT patients, including hyperventilation, breath-holding, heart rate, and constipation. These and other observations suggest that serotonin - a chemical messenger in the brain that affects emotions, behavior, and thoughts - may be involved in modulating these disturbances. In this report, the authors compared a small population of autopsied RTT and non-RTT patients to look for differences in the serotonin system in the medulla - a part of the brain that controls the autonomic nervous system. Surprisingly, no major differences were found in this comparison. However, there was a marginal difference in one part of the medulla - the dorsal motor nucleus of the vagus (DMX) - which plays a role in heart rate regulation. These findings are valuable as they allow for the generation of hypotheses for testing in Rett mouse models to better understand the underlying molecular mechanisms involving serotonin, DMX, and Rett syndrome. This work was funded in part by RSRF.