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Dopaminergic abnormalities in Hdac6-deficient mice.

Publication ,  Journal Article
Fukada, M; Nakayama, A; Mamiya, T; Yao, T-P; Kawaguchi, Y
Published in: Neuropharmacology
November 2016

Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders. Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing postsynaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia.

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Published In

Neuropharmacology

DOI

EISSN

1873-7064

Publication Date

November 2016

Volume

110

Issue

Pt A

Start / End Page

470 / 479

Location

England

Related Subject Headings

  • Schizophrenia
  • Receptors, Dopamine D2
  • Receptors, Dopamine D1
  • RNA, Messenger
  • Neurology & Neurosurgery
  • Motor Activity
  • Mice, Knockout
  • Mice, 129 Strain
  • Methamphetamine
  • Male
 

Citation

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Fukada, M., Nakayama, A., Mamiya, T., Yao, T.-P., & Kawaguchi, Y. (2016). Dopaminergic abnormalities in Hdac6-deficient mice. Neuropharmacology, 110(Pt A), 470–479. https://doi.org/10.1016/j.neuropharm.2016.08.018
Fukada, Masahide, Atsuo Nakayama, Takayoshi Mamiya, Tso-Pang Yao, and Yoshiharu Kawaguchi. “Dopaminergic abnormalities in Hdac6-deficient mice.Neuropharmacology 110, no. Pt A (November 2016): 470–79. https://doi.org/10.1016/j.neuropharm.2016.08.018.
Fukada M, Nakayama A, Mamiya T, Yao T-P, Kawaguchi Y. Dopaminergic abnormalities in Hdac6-deficient mice. Neuropharmacology. 2016 Nov;110(Pt A):470–9.
Fukada, Masahide, et al. “Dopaminergic abnormalities in Hdac6-deficient mice.Neuropharmacology, vol. 110, no. Pt A, Nov. 2016, pp. 470–79. Pubmed, doi:10.1016/j.neuropharm.2016.08.018.
Fukada M, Nakayama A, Mamiya T, Yao T-P, Kawaguchi Y. Dopaminergic abnormalities in Hdac6-deficient mice. Neuropharmacology. 2016 Nov;110(Pt A):470–479.
Journal cover image

Published In

Neuropharmacology

DOI

EISSN

1873-7064

Publication Date

November 2016

Volume

110

Issue

Pt A

Start / End Page

470 / 479

Location

England

Related Subject Headings

  • Schizophrenia
  • Receptors, Dopamine D2
  • Receptors, Dopamine D1
  • RNA, Messenger
  • Neurology & Neurosurgery
  • Motor Activity
  • Mice, Knockout
  • Mice, 129 Strain
  • Methamphetamine
  • Male