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Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice
Agnieszka Krzyzosiak1, Monika Szyszka-Niagolov, Marta Wietrzych
1IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), BP 10142, Inserm, U 596, CNRS, UMR 7104 Illkirch F-67400, France.
Abstract:
Abnormal signaling by retinoids or n-3 polyunsaturated fatty acids has been implicated in clinical depression. The converging point in activities of these two classes of molecules is transcriptional activation of retinoid X receptors (Rxr). We show here that ablation of Rxrgamma in mice leads to depressive-like behaviors including increased despair and anhedonia, which were accompanied by reduced expression of dopamine D2 receptor in the shell of nucleus accumbens (NAc) and altered serotonin signaling. While abnormal serotonin signaling is not sufficient to generate the depressive behaviors, increasing D2r expression by chronic fluoxetine (Prozac) treatment or adenoassociated virus type2 (AAV2) mediated expression of Rxrgamma or D2r in the NAc of Rxrgamma(-/-) mice normalizes depressive-like behaviors in Rxrgamma(-/-) animals. Conversely, NAc infusion of raclopride, a D2r antagonist prevents AAV2-Rxrgamma-mediated rescue of despair behaviors in Rxrgamma(-/-) mice. Combined, our data argue that control of NAc D2r expression is critical for Rxrgamma-mediated modulation of affective behaviors.
Insights
Retinoid X receptor gamma (Rxrgamma) deficiency in mice causes depression-like behaviors. Restoring dopamine D2 receptor (D2r) expression in the nucleus accumbens (NAc) rescues these behaviors, highlighting Rxrgamma
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- Abnormal signaling of retinoids and n-3 polyunsaturated fatty acids is linked to clinical depression.
- Both molecular pathways converge on the transcriptional activation of retinoid X receptors (Rxr).
Purpose of the Study:
- To investigate the role of Rxrgamma in depressive-like behaviors.
- To elucidate the molecular mechanisms underlying Rxrgamma's influence on affective behaviors.
Main Methods:
- Generation of Rxrgamma-ablated mice (Rxrgamma(-/-)).
- Assessment of depressive-like behaviors (despair, anhedonia).
- Analysis of dopamine D2 receptor (D2r) and serotonin signaling in the nucleus accumbens (NAc).
- Pharmacological and viral vector-mediated interventions (fluoxetine, AAV2-mediated Rxrgamma/D2r expression, raclopride).
Main Results:
- Rxrgamma ablation in mice induced depressive-like behaviors.
- These behaviors correlated with reduced NAc D2r expression and altered serotonin signaling.
- Restoring NAc D2r expression via fluoxetine or AAV2-Rxrgamma/D2r normalized depressive behaviors.
- D2r antagonism blocked Rxrgamma-mediated behavioral rescue.
Conclusions:
- Rxrgamma plays a critical role in modulating affective behaviors.
- Control of dopamine D2 receptor expression in the NAc is essential for Rxrgamma's effects on depression.
- This study identifies a novel molecular pathway involving Rxrgamma and D2r in the neurobiology of depression.
