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Title: Cyclin-Dependent Kinase 5 Dysfunction Contributes to Depressive-like Behaviors in Huntington's Disease by Altering the DARPP-32 Phosphorylation Status in the Nucleus Accumbens
Author: Brito, Verónica
Giralt Torroella, Albert
Masana Nadal, Mercè
Royes, Aida
Espina, Marc
Sieiro, Esther
Alberch i Vié, Jordi
Castañé, Anna
Girault, Jean-Antoine
Ginés Padrós, Silvia
Keywords: Corea de Huntington
Depressió psíquica
Huntington's chorea
Mental depression
Issue Date: 1-Aug-2019
Publisher: Elsevier B.V.
Abstract: Background: Depression is the most common psychiatric condition in Huntington's disease (HD), with rates more than twice those found in the general population. At the present time, there is no established molecular evidence to use as a basis for depression treatment in HD. Indeed, in some patients, classic antidepressant drugs exacerbate chorea or anxiety. Cyclin-dependent kinase 5 (Cdk5) has been involved in processes associated with anxiety and depression. This study evaluated the involvement of Cdk5 in the development and prevalence of depressive-like behaviors in HD and aimed to validate Cdk5 as a target for depression treatment. Methods: We evaluated the impact of pharmacological inhibition of Cdk5 in depressive-like and anxiety-like behaviors in Hdh+/Q111 knock-in mutant mice by using a battery of behavioral tests. Biochemical and morphological studies were performed to define the molecular mechanisms acting downstream of Cdk5 activation. A double huntingtin/DARPP-32 (dopamine- and cAMP-regulated phosphoprotein 32) knock-in mutant mouse was generated to analyze the role of DARPP-32 in HD depression. Results: We found that Hdh+/Q111 mutant mice exhibited depressive-like, but not anxiety-like, behaviors starting at 2 months of age. Cdk5 inhibition by roscovitine infusion prevented depressive-like behavior and reduced DARPP-32 phosphorylation at Thr75 in the nucleus accumbens. Hdh+/Q111 mice heterozygous for DARPP-32 Thr75Ala point mutation were resistant to depressive-like behaviors. We identified β-adducin phosphorylation as a Cdk5 downstream mechanism potentially mediating structural spine plasticity changes in the nucleus accumbens and depressive-like behavior. Conclusions: These results point to Cdk5 in the nucleus accumbens as a critical contributor to depressive-like behaviors in HD mice by altering DARPP-32/β-adducin signaling and disrupting the dendritic spine cytoskeleton.
Note: Versió postprint del document publicat a:
It is part of: Biological Psychiatry, 2019, vol. 86, num. 3, p. 196-207
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ISSN: 0006-3223
Appears in Collections:Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Neurociències (UBNeuro))
Articles publicats en revistes (Biomedicina)

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