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.
Keywords
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Article Info
Publication History
Published online: March 12, 2019
Accepted:
March 4,
2019
Received in revised form:
February 15,
2019
Received:
October 26,
2018
Identification
Copyright
© 2019 Society of Biological Psychiatry.
