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

Biol Psychiatry. 2019 Aug 1;86(3):196-207. doi: 10.1016/j.biopsych.2019.03.001. Epub 2019 Mar 13.


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.

Keywords: Cdk5; DARPP-32; Dendritic spines; Depressive-like behavior; Huntington’s disease; β-adducin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclin-Dependent Kinase 5 / genetics
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Cytoskeletal Proteins / metabolism
  • Dendritic Spines / metabolism
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / genetics
  • Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism*
  • Female
  • Huntington Disease / enzymology*
  • Male
  • Mice
  • Mice, Neurologic Mutants
  • Neural Pathways / physiopathology
  • Nucleus Accumbens / metabolism*
  • Phosphorylation


  • Add2 protein, mouse
  • Cytoskeletal Proteins
  • Dopamine and cAMP-Regulated Phosphoprotein 32
  • Ppp1r1b protein, mouse
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse