TY - JOUR
T1 - Loss of MeCP2 in adult 5-HT neurons induces 5-HT1A autoreceptors, with opposite sex-dependent anxiety and depression phenotypes
AU - Philippe, Tristan J.
AU - Vahid-Ansari, Faranak
AU - Donaldson, Zoe R.
AU - Le François, Brice
AU - Zahrai, Amin
AU - Turcotte-Cardin, Valérie
AU - Daigle, Mireille
AU - James, Jonathan
AU - Hen, René
AU - Merali, Zul
AU - Albert, Paul R.
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner.
AB - The 5-HT1A autoreceptor mediates feedback inhibition of serotonin (5-HT) neurons, and is implicated in major depression. The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription. Since chronic stress alters HTR1A methylation and expression, we addressed whether recruitment of methyl-binding protein MeCP2 may alter Deaf1 regulation at the HTR1A locus. We show that MeCP2 enhances Deaf1 binding to its HTR1A site and co-immunoprecipitates with Deaf1 in cells and brain tissue. Chromatin immunoprecipitation assays showed Deaf1-dependent recruitment of MeCP2 to the mouse HTR1A promoter, and MeCP2 modulated human and mouse HTR1A gene transcription in a Deaf1-dependent fashion, enhancing Deaf1-induced repression at the Deaf1 site. To address the role of MeCP2 in HTR1A regulation in vivo, mice with conditional knockout of MeCP2 in adult 5-HT neurons (MeCP2 cKO) were generated. These mice exhibited increased 5-HT1A autoreceptor levels and function, consistent with MeCP2 enhancement of Deaf1 repression in 5-HT neurons. Interestingly, female MeCP2-cKO mice displayed reduced anxiety, while males showed increased anxiety and reduced depression-like behaviors. These data uncover a novel role for MeCP2 in 5-HT neurons to repress HTR1A expression and drive adult anxiety- and depression-like behaviors in a sex-specific manner.
UR - http://www.scopus.com/inward/record.url?scp=85045279622&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-24167-8
DO - 10.1038/s41598-018-24167-8
M3 - Article
C2 - 29636529
AN - SCOPUS:85045279622
SN - 2045-2322
VL - 8
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 5788
ER -