Antidepressant Fluoxetine Increases Cells With MeCP2 in Mouse Model
Treatment with fluoxetine, a type of antidepressant sold under the brand name Prozac, increased the number of cells producing the protein MeCP2 — defective in most cases of Rett syndrome — in several brain regions of a mouse model of the disease, a study reported.
These effects were prevented by suppressing the production of serotonin, a chemical messenger between nerve cells.
The findings suggest that boosting serotonin production may be enough to increase the levels of MeCP2 in the brain and rescue motor impairment.
The study, “Fluoxetine increases brain MeCP2 immuno-positive cells in a female Mecp2 heterozygous mouse model of Rett syndrome through endogenous serotonin,” was published in the journal Scientific Reports.
Mutations of the MECP2 gene are the leading cause of Rett syndrome. This gene encodes for MeCP2, a protein that is abundant in mature brain cells and regulates the expression (activity) of other genes. Both the over- and underproduction of MeCP2 lead to severe neurological issues.
Several recent therapeutic approaches have attempted to deliver a working copy of the MECP2 gene. Although some have produced promising results in animal studies, the feasibility, efficacy, and safety of these therapies have not yet been shown in Rett syndrome patients.
The researchers behind the current study, from Milan, Italy, had previously reported that fluoxetine, a serotonin reuptake inhibitor (SSRI) antidepressant, increased the Mecp2 gene activity in two regions of the rat brain — the striatum and the frontal cortex, both implicated in the control of movement. The antidepressant also had been found to enhance MeCP2 levels in the brain of a mouse model of Down syndrome. In addition, fluoxetine rescued the lack of motor coordination in female mice engineered to mimic Rett syndrome.
Now, the researchers used the same mouse model of Rett to understand whether the motor effects of fluoxetine are derived from its ability to enhance serotonin, its capacity to promote the expression of MeCP2, or both.
The team first observed that mice with mutations in Mecp2 — the mouse version of MECP2 — had a significantly lower number of MeCP2-expressing cells in the brain than did healthy mice, used as controls. All examined brain areas showed this difference, including subregions of the striatum, the motor cortex, and the prefrontal cortex or PFC. The PFC plays a key role in cognition and goal-directed behavior.
Treatment with 10 mg/kg fluoxetine, given once a day for 14 days, increased the number of MeCP2-expressing cells to 70% of those in control mice in the PFC, 64% to 72% in different regions of the motor cortex, and 59% to 62% in areas of the striatum. However, fluoxetine had no effect in the CA3 region of the hippocampus, implicated in memory.
Using statistical analyses, the researchers searched for an association between rotarod performance, a test of motor coordination in rodents, and the number of MeCP2-expressing cells in various brain regions. The findings showed a significant correlation only in the PFC.
According to the team, this suggests that “increased MeCP2 in the PFC may underlie [fluoxetine]’s ability to improve rotarod performance.”
To determine the role of serotonin in fluoxetine’s effects, mice were given 100 mg/kg pCPA orally with or without fluoxetine, for three days. Notably, pCPA is a serotonin production inhibitor. Lack of serotonin reversed fluoxetine’s impact in increasing the number of MeCP2-expressing cells.
“These findings suggest that boosting [serotonin] transmission is sufficient to enhance the expression of MeCP2 in several brain regions of [Rett mice]. Fluoxetine-induced rise of MeCP2 could potentially rescue motor coordination and other deficits of [Rett syndrome].” the scientists wrote.
The researchers noted that a clinical study launched in 2008 to test the effects of fluoxetine in people with Rett syndrome was ended prematurely (EudraCT Number: 2008-000787-16), and that no other clinical evaluations of SSRIs in Rett syndrome have been reported. As such, further studies are needed to investigate the efficacy of SSRIs in Rett patients, the team said.