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Mice lacking p35 display hyperactivity and paradoxical response to psychostimulants
Favio Ariel Krapacher1, Estela Cecilia Mlewski, Soledad Ferreras
1Laboratory of Neurobiology and Cell Biology, Instituto de Investigación Médica Mercedes y Martín Ferreyra (INIMEC-CONICET), 5016 Córdoba, Argentina.
Journal of Neurochemistry
|April 21, 2010
Summary
Juvenile mice lacking p35 protein showed hyperactivity and altered dopamine signaling, suggesting a role for cyclin-dependent kinase 5 (Cdk5) in motor control and attention deficit hyperactivity disorder (ADHD).
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Genetics
Background:
- Dopamine (DA) signaling is crucial for neurotransmission, and its dysregulation is linked to neurological disorders.
- Cyclin-dependent kinase 5 (Cdk5) activity is essential for normal brain function, requiring association with its activator, p35.
- Altered Cdk5 activity may impact striatal-mediated behaviors and contribute to neuropsychiatric conditions.
Purpose of the Study:
- To investigate the role of p35 protein deficiency and its impact on Cdk5 activity in striatal-mediated behavior.
- To characterize the behavioral and biochemical phenotype of p35 knockout (p35 KO) mice, particularly during juvenile stages.
- To explore the potential of p35 KO mice as a model for attention deficit hyperactivity disorder (ADHD)-like disorders.
Main Methods:
- Utilized p35 knockout (p35 KO) mice exhibiting reduced Cdk5 activity.
- Conducted comprehensive behavioral analyses on naïve and psychostimulant-treated juvenile mice.
- Performed biochemical assessments, including immunolabeling for tyrosine-hydroxylase and measurement of striatal dopamine synthesis, content, and turnover.
Main Results:
- Juvenile p35 KO mice displayed spontaneous hyperactivity and paradoxical hypolocomotor responses to psychostimulants.
- These mice exhibited deficits in behavioral inhibition and altered dopamine system function, including high striatal DA synthesis and content with low turnover.
- Psychostimulant administration reverted these biochemical alterations in mutant mice.
- p35 deficiency was critically linked to a hyperactive phenotype and an overactive dopaminergic system.
Conclusions:
- p35 deficiency significantly contributes to a hyperactive behavioral phenotype and dopaminergic system hyperfunction.
- Proper Cdk5 kinase activity is vital for normal motor and emotional regulation.
- p35 KO mice represent a valuable model for studying the molecular underpinnings of ADHD-like disorders.
