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Impaired locomotion and dopamine signaling in retinoid receptor mutant mice
W Krezel1, N Ghyselinck, T A Samad
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université Louis Pasteur, Collège de France, Boite Postale 163, 67404 Illkirch Cedex, France.
Abstract:
In the adult mouse, single and compound null mutations in the genes for retinoic acid receptor beta and retinoid X receptors beta and gamma resulted in locomotor defects related to dysfunction of the mesolimbic dopamine signaling pathway. Expression of the D1 and D2 receptors for dopamine was reduced in the ventral striatum of mutant mice, and the response of double null mutant mice to cocaine, which affects dopamine signaling in the mesolimbic system, was blunted. Thus, retinoid receptors are involved in the regulation of brain functions, and retinoic acid signaling defects may contribute to pathologies such as Parkinson's disease and schizophrenia.
Insights
Retinoid receptors regulate brain dopamine pathways. Defects in retinoic acid signaling may contribute to Parkinson's disease and schizophrenia by causing locomotor issues.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Retinoid receptors, including retinoic acid receptor beta (RARβ) and retinoid X receptors (RXRs) beta and gamma, play crucial roles in cellular differentiation and development.
- The mesolimbic dopamine pathway is vital for motor control, reward, and motivation.
- Dysfunction in dopamine signaling is implicated in various neurological and psychiatric disorders.
Purpose of the Study:
- To investigate the role of retinoid receptors (RARβ, RXRβ, RXRγ) in regulating the mesolimbic dopamine signaling pathway in adult mice.
- To determine the impact of genetic mutations in these receptors on locomotor activity and dopamine receptor expression.
- To explore the potential link between retinoid signaling defects and neurological conditions.
Main Methods:
- Generation of single and compound null mutant mice for RARβ, RXRβ, and RXRγ genes.
- Assessment of locomotor behavior in mutant mice.
- Measurement of dopamine D1 and D2 receptor expression in the ventral striatum.
- Evaluation of mutant mice response to cocaine administration.
Main Results:
- Single and compound null mutations in RARβ, RXRβ, and RXRγ genes led to significant locomotor defects.
- Mutant mice exhibited reduced expression of dopamine D1 and D2 receptors in the ventral striatum.
- The response to cocaine was blunted in double null mutant mice, indicating impaired mesolimbic dopamine pathway function.
Conclusions:
- Retinoid receptors are essential regulators of brain functions, particularly the mesolimbic dopamine signaling pathway.
- Defects in retinoic acid signaling can cause locomotor dysfunction.
- These findings suggest that retinoic acid signaling deficits may contribute to the pathophysiology of diseases like Parkinson's disease and schizophrenia.