Analysis of the Serotonergic System in a Mouse Model of Rett Syndrome Reveals Unusual Upregulation of Serotonin Receptor 5b.
Mutations in the transcription factor methyl-CpG-binding-protein 2 (MeCP2) cause a delayed-onset neurodevelopmental disorder known as Rett syndrome (RTT). Although alteration in serotonin levels have been reported in RTT patients, the molecular mechanisms underlying these defects are not well understood. Therefore, we chose to investigate the serotonergic system in hippocampus and brainstem of maleMecp2-/yknock-out mice in the B6.129P2(C)-Mecp2(tm1.1Bird) mouse model of RTT. The serotonergic system in mouse is comprised of 16 genes, whose mRNA expression profile was analyzed by quantitative RT-PCR.Mecp2-/ymice are an established animal model for RTT displaying most of the cognitive and physical impairments of human patients and the selected areas receive significant modulation through serotonin. Using anatomically and functional characterized areas, we found region-specific differential expression between wild type andMecp2-/ymice at post-natal day 40. In brainstem, we found five genes to be dysregulated, while in hippocampus, two genes were dysregulated. The one gene dysregulated in both brain regions was dopamine decarboxylase, but of special interest is the serotonin receptor 5b (5-ht5b), which showed 75-fold dysregulation in brainstem ofMecp2-/ymice. This dysregulation was not due to upregulation, but due to failure of down-regulation inMecp2-/ymice during development. Detailed analysis of 5-ht5brevealed a receptor that localizes to endosomes and interacts with Gαiproteins.
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the Brain Göttingen, Germany.
Steffen
S
Vogelgesang
Department of Maxillofacial Surgery, University Medical Center Göttingen, Germany.
Sabine
S
Niebert
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the Brain Göttingen, Germany.
Ute
U
Renner
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the BrainGöttingen, Germany; Department of Neurogenetics, Max Planck Institute of Experimental MedicineGöttingen, Germany.
Wiebke
W
Möbius
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the BrainGöttingen, Germany; Clinic for Anesthesiology, University Medical CenterGöttingen, Germany.
Swen
S
Hülsmann
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the Brain Göttingen, Germany.
Till
T
Manzke
DFG Research Center and Excellence Cluster Microscopy at the Nanometer Range and Molecular Physiology of the BrainGöttingen, Germany; Institute of Neuro- and Sensory Physiology, University Medical CenterGöttingen, Germany.
Marcus
M
Niebert
5-HT receptors; 5-ht5b receptor; MeCP2; Rett syndrome (RTT); mouse models; serotonin