title: Serotonin transporter abnormality in the dorsal motor nucleus of the vagus in Rett syndrome: potential implications for clinical autonomic dysfunction.
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 [(125)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.
authors.affiliation: Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA. david.paterson@childrens.harvard.edu
authors.forename: David S
authors.initials: DS
authors.lastname: Paterson
authors.forename: Eric G
authors.initials: EG
authors.lastname: Thompson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Belliveau
authors.forename: Bobbie A
authors.initials: BA
authors.lastname: Antalffy
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.forename: Dawna D
authors.initials: DD
authors.lastname: Armstrong
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kinney
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D001345:Autoradiography / Q000379:methods; D002452:Cell Count / Q000379:methods; D002648:Child; D002675:Child, Preschool; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007456:Iodine Isotopes / Q000493:pharmacokinetics; D008526:Medulla Oblongata / Q000473:pathology*; D009474:Neurons / Q000378:metabolism*; D015518:Rett Syndrome / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D014018:Tissue Distribution / Q000187:drug effects; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014630:Vagus Nerve / Q000503:physiopathology*
chemical_list: D007456:Iodine Isotopes; D050486:Serotonin Plasma Membrane Transport Proteins; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D014365:Tryptophan Hydroxylase; D003042:Cocaine