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Distinctive behavioral and cellular responses to fluoxetine in the mouse model for Fragile X syndrome
Marko Uutela1, Jesse Lindholm2, Tomi Rantamäki2
1Institute of Biomedicine/Physiology, University of Helsinki Helsinki, Finland.
Abstract:
Fluoxetine is used as a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS). The treatment often associates with disruptive behaviors such as agitation and disinhibited behaviors in FXS. To identify mechanisms that increase the risk to poor treatment outcome, we investigated the behavioral and cellular effects of fluoxetine on adult Fmr1 knockout (KO) mice, a mouse model for FXS. We found that fluoxetine reduced anxiety-like behavior of both wild-type and Fmr1 KO mice seen as shortened latency to enter the center area in the open field test. In Fmr1 KO mice, fluoxetine normalized locomotor hyperactivity but abnormally increased exploratory activity. Reduced brain-derived neurotrophic factor (BDNF) and increased TrkB receptor expression levels in the hippocampus of Fmr1 KO mice associated with inappropriate coping responses under stressful condition and abolished antidepressant activity of fluoxetine. Fluoxetine response in the cell proliferation was also missing in the hippocampus of Fmr1 KO mice when compared with wild-type controls. The postnatal mRNA expression of serotonin transporter (SERT) was reduced in the thalamic nuclei of Fmr1 KO mice during the time of transient innervation of somatosensory neurons suggesting that developmental changes of SERT expression were involved in the differential cellular and behavioral responses to fluoxetine in wild-type and Fmr1 mice. The results indicate that changes of BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine among individuals with ASD.
Insights
Fluoxetine treatment for autism spectrum disorder (ASD) shows varied responses in Fragile X syndrome (FXS) models. Altered brain-derived neurotrophic factor (BDNF) signaling in Fmr1 knockout mice impacts fluoxetine
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Fluoxetine is a therapeutic agent for autism spectrum disorder (ASD), including Fragile X syndrome (FXS).
- Individuals with FXS often exhibit disruptive behaviors like agitation and disinhibition during fluoxetine treatment.
- Identifying mechanisms for poor treatment outcomes in FXS is crucial.
Purpose of the Study:
- To investigate the behavioral and cellular effects of fluoxetine in adult Fmr1 knockout (KO) mice, a model for FXS.
- To understand how altered neurobiology in FXS influences fluoxetine's efficacy and side effects.
Main Methods:
- Administered fluoxetine to adult wild-type and Fmr1 KO mice.
- Assessed anxiety-like behavior using the open field test.
- Measured locomotor activity and exploratory behavior.
- Analyzed hippocampal expression of brain-derived neurotrophic factor (BDNF) and TrkB receptors.
- Investigated cell proliferation in the hippocampus.
- Examined postnatal serotonin transporter (SERT) mRNA expression in thalamic nuclei.
Main Results:
- Fluoxetine reduced anxiety in both wild-type and Fmr1 KO mice.
- In Fmr1 KO mice, fluoxetine normalized hyperactivity but increased exploratory activity.
- Reduced hippocampal BDNF and increased TrkB in Fmr1 KO mice correlated with poor stress coping and abolished antidepressant effects.
- Fluoxetine-induced cell proliferation was absent in Fmr1 KO mouse hippocampus.
- Reduced postnatal SERT mRNA expression in Fmr1 KO mice suggests developmental involvement.
Conclusions:
- Changes in BDNF/TrkB signaling contribute to differential behavioral responses to fluoxetine in individuals with ASD.
- Developmental alterations in SERT expression may underlie varied responses to fluoxetine in FXS.
- Fmr1 KO mice provide a valuable model for studying fluoxetine's complex effects in FXS.
