A mouse model of Rett syndrome shows a cell-autonomous reduction of α4* nicotinic receptors in dopaminergic neurons of the substantia nigra pars compacta
Date
2018
Authors
Le Gratiet, Keyrian
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Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder due to spontaneous mutations in a gene (MECP2) on the X chromosome. With the mutations typically found in the paternal germline, female RTT patient are more common than males and manifest a constellation of severely debilitating symptoms after birth. Development is mostly normal during the first 6 months but then stalls and regresses resulting in individuals that lack motor coordination, have impaired speech, and exhibit Parkinsonian symptoms often accompanied by seizures. Mice with the same mutation have many neuronal dysfunctions including poor neural communication, some of which is due to improper signaling by the transmitter acetylcholine (ACh). The cholinergic system is critically involved in the generation of purposeful behaviours including voluntary motor acts, which correlate with some of the conditions seen in RTT patients. The present study investigated whether mutant (Mecp2-) dopaminergic (DAergic) cells have downregulated α4-containing (α4*) nicotinic acetylcholine receptor (nAChRs) expression compared to wild-type (Wt) (Mecp2+) DAergic cells in the substantia nigra pars compacta (SNc) of a RTT female mouse and whether this downregulation was cell-autonomous. Spectral confocal imaging was used to quantify the YFP-tagged α4* nAChRs in five-week-old Mecp2EGFP/+/ α4YFP/+, Mecp2+/- / α4YFP/+, and Mecp2+/+ / α4YFP/+ female mice. Imaging confirms that mutant DAergic neurons have reduced expression of α4* nAChRs compared to spatially colocalized Wt DAergic neurons in the SNc of a young RTT female mouse. Furthermore, the reduction in nAChR expression in DAergic neurons was found to be cellautonomous with Wt DAergic neurons from the RTT female and DAergic neurons from Wt females displaying similar amounts of α4* nAChRs on their soma. Finally, there was convincing evidence for spatially-modulated reduction in nAChR expression in mutant DAergic neurons with the lateral SNc showing a greater reduction in levels of nAChR expression compared to the medial SNc. To our knowledge, this is the first study to provide anatomical evidence for a cellautonomous downregulation of α4* nAChR expression in DAergic neurons in the SNc of a young RTT female mouse.