Sex Differences in Dopamine Receptor Signaling in Fmr1 Knockout Mice: A Pilot Study.

Anlong Jiang,Fang Liu,Amy Freeman,Charlie Campbell,Justin Y D Lu,Le Wang,Albert H C Wong,Ping Su

doi:10.3390/brainsci11111398

Anlong Jiang, Fang Liu + Show 6 more

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https://doi.org/10.3390/brainsci11111398

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Abstract

Fragile X syndrome (FXS) is an X-chromosome-linked dominant genetic disorder that causes a variable degree of cognitive dysfunction and developmental disability. Current treatment is symptomatic and no existing medications target the specific cause of FXS. As with other X-linked disorders, FXS manifests differently in males and females, including abnormalities in the dopamine system that are also seen in Fmr1-knockout (KO) mice. We investigated sex differences in dopamine signaling in Fmr1-KO mice in response to L-stepholidine, a dopamine D1 receptor agonist and D2 receptor antagonist. We found significant sex differences in basal levels of phosphorylated protein kinase A (p-PKA) and glycogen synthase kinase (GSK)-3β in wild type mice that were absent in Fmr1-KO mice. In wild-type mice, L-stepholidine increased p-PKA in males but not female mice, decreased p-GSK-3 in female mice and increased p-GSK-3 in male mice. Conversely, in Fmr1-KO mice, L-stepholidine increased p-PKA and p-GSK-3β in females, and decreased p-PKA and p-GSK-3β in males.

Highlights

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by mutation of the fragile X mental retardation (FMR1) gene that leads to insufficiency of the fragile X mental retardation protein (FMRP) [1,2]
FXS results from mutations in the fragile X mental retardation 1 (Fmr1) gene located at chromosome Xq27.3 that encodes FMRP
In addition to classical dopamine receptor signaling through G-proteins, the dopamine D2like receptors regulate protein kinase B (Akt) through beta-arrestin 2 and glycogen synthase kinase 3β (GSK-3β) [29,30], which we examined in this paper

Summary

Introduction

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism, caused by mutation of the fragile X mental retardation (FMR1) gene that leads to insufficiency of the fragile X mental retardation protein (FMRP) [1,2]. FXS includes a spectrum of clinical manifestations, ranging from learning disabilities, attention deficits and hyperactivity to severe intellectual disability with autistic symptoms [3,4,5]. Medications for FXS-associated seizures, mood dysregulation, hyperactivity, and attention deficits [8,9]. FXS results from mutations in the fragile X mental retardation 1 (Fmr1) gene located at chromosome Xq27.3 that encodes FMRP. The most common Fmr mutation leading to FMRP deficiency is a trinucleotide repeat expansion, consisting of a CGG in the 50 untranslated region (50 -UTR). The trinucleotide expansion triggers the methylation of CGG sequences and the FMR1 promoter along with deacetylation of associated histones and

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