RT Journal Article
SR Electronic
T1 Total RNA-sequencing of Rett Syndrome Autopsy Samples Identifies the M4 Muscarinic Receptor as a Novel Therapeutic Target
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.117.246991
DO 10.1124/jpet.117.246991
A1 Rocco Gogliotti
A1 Nicole Fisher
A1 Branden Stansley
A1 Carrie Jones
A1 Craig Lindsley
A1 Jeffrey Conn
A1 Colleen Niswender
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/03/09/jpet.117.246991.abstract
AB Mutations in the Methyl CpG Binding Protein 2 (MECP2) gene are responsible for the neurodevelopmental disorder Rett syndrome (RTT). MeCP2 is a DNA-binding protein whose abundance and ability to complex with HDAC3 is linked to the regulation of chromatin structure. Consequently, loss-of-function mutations in MeCP2 are predicted to have broad effects on gene expression. However, to date, studies in mouse models of RTT have identified a limited number of gene or pathway-level disruptions, and even fewer genes have been identified that could be considered amenable to classical drug discovery approaches. Here, we performed RNA-sequencing (seq) on 9 motor cortex and 6 cerebellar autopsy samples from RTT patients and controls. This approach identified 1,883 significantly affected genes in the motor cortex and 2,110 genes in the cerebellum, with a global trend towards increased expression. Pathway-level analysis identified enrichment in genes associated with MAPK-signaling, long-term potentiation, and axon guidance. A survey of our RNA-seq results also identified a significant decrease in expression of the muscarinic acetylcholine receptor 4 (CHRM4) gene, which encodes a receptor (M4) that is the subject of multiple large drug discovery efforts for schizophrenia and Alzheimer's disease. We confirmed that CHRM4 expression was decreased in RTT patients, and, excitingly, we demonstrated that M4 potentiation normalizes social and cognitive phenotypes in Mecp2+/- mice. This work provides an experimental paradigm in which translationally relevant targets can be identified using transcriptomics in RTT autopsy samples, back-modeled in Mecp2+/- mice, and assessed for preclinical efficacy using existing pharmacological tool compounds.