Human Mutant Huntingtin Disrupts Vocal Learning in Transgenic Songbirds

Overview

Journal Nat Neurosci

Date 2015 Oct 6

PMID 26436900

Citations 17

Authors

Wan-Chun Liu

Jessica Kohn

Sarah K Szwed

Eben Pariser

Sharon Sepe

Bhagwattie Haripal

Naoki Oshimori

Martin Marsala

Atsushi Miyanohara

Ramee Lee

Affiliations

Soon will be listed here.

Abstract

Speech and vocal impairments characterize many neurological disorders. However, the neurogenetic mechanisms of these disorders are not well understood, and current animal models do not have the necessary circuitry to recapitulate vocal learning deficits. We developed germline transgenic songbirds, zebra finches (Taneiopygia guttata) expressing human mutant huntingtin (mHTT), a protein responsible for the progressive deterioration of motor and cognitive function in Huntington's disease (HD). Although generally healthy, the mutant songbirds had severe vocal disorders, including poor vocal imitation, stuttering, and progressive syntax and syllable degradation. Their song abnormalities were associated with HD-related neuropathology and dysfunction of the cortical-basal ganglia (CBG) song circuit. These transgenics are, to the best of our knowledge, the first experimentally created, functional mutant songbirds. Their progressive and quantifiable vocal disorder, combined with circuit dysfunction in the CBG song system, offers a model for genetic manipulation and the development of therapeutic strategies for CBG-related vocal and motor disorders.

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References

Menalled L . Knock-in mouse models of Huntington's disease. NeuroRx. 2006; 2(3):465-70. PMC: 1144489. DOI: 10.1602/neurorx.2.3.465. View

Sharp A, Loev S, Schilling G, Li S, Li X, Bao J . Widespread expression of Huntington's disease gene (IT15) protein product. Neuron. 1995; 14(5):1065-74. DOI: 10.1016/0896-6273(95)90345-3. View

DiFiglia M, Sapp E, Chase K, Davies S, Bates G, Vonsattel J . Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997; 277(5334):1990-3. DOI: 10.1126/science.277.5334.1990. View

Harper S, Staber P, He X, Eliason S, Martins I, Mao Q . RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc Natl Acad Sci U S A. 2005; 102(16):5820-5. PMC: 556303. DOI: 10.1073/pnas.0501507102. View

Liu W, Wada K, Jarvis E, Nottebohm F . Rudimentary substrates for vocal learning in a suboscine. Nat Commun. 2013; 4:2082. DOI: 10.1038/ncomms3082. View

Chen Q, Heston J, Burkett Z, White S . Expression analysis of the speech-related genes FoxP1 and FoxP2 and their relation to singing behavior in two songbird species. J Exp Biol. 2013; 216(Pt 19):3682-92. PMC: 3763803. DOI: 10.1242/jeb.085886. View

Scharff C, Nottebohm F . A comparative study of the behavioral deficits following lesions of various parts of the zebra finch song system: implications for vocal learning. J Neurosci. 1991; 11(9):2896-913. PMC: 6575264. View

Pytte C, George S, Korman S, David E, Bogdan D, Kirn J . Adult neurogenesis is associated with the maintenance of a stereotyped, learned motor behavior. J Neurosci. 2012; 32(20):7052-7. PMC: 3407572. DOI: 10.1523/JNEUROSCI.5385-11.2012. View

Kubikova L, Kostal L . Dopaminergic system in birdsong learning and maintenance. J Chem Neuroanat. 2009; 39(2):112-23. PMC: 2822041. DOI: 10.1016/j.jchemneu.2009.10.004. View

10.

Olveczky B, Andalman A, Fee M . Vocal experimentation in the juvenile songbird requires a basal ganglia circuit. PLoS Biol. 2005; 3(5):e153. PMC: 1069649. DOI: 10.1371/journal.pbio.0030153. View

11.

Arrasate M, Finkbeiner S . Protein aggregates in Huntington's disease. Exp Neurol. 2011; 238(1):1-11. PMC: 3909772. DOI: 10.1016/j.expneurol.2011.12.013. View

12.

Zuccato C, Valenza M, Cattaneo E . Molecular mechanisms and potential therapeutical targets in Huntington's disease. Physiol Rev. 2010; 90(3):905-81. DOI: 10.1152/physrev.00041.2009. View

13.

Wada K, Hayase S, Imai R, Mori C, Kobayashi M, Liu W . Differential androgen receptor expression and DNA methylation state in striatum song nucleus Area X between wild and domesticated songbird strains. Eur J Neurosci. 2013; 38(4):2600-10. DOI: 10.1111/ejn.12258. View

14.

Agate R, Scott B, Haripal B, Lois C, Nottebohm F . Transgenic songbirds offer an opportunity to develop a genetic model for vocal learning. Proc Natl Acad Sci U S A. 2009; 106(42):17963-7. PMC: 2764872. DOI: 10.1073/pnas.0909139106. View

15.

Chen J, Wang E, Cepeda C, Levine M . Dopamine imbalance in Huntington's disease: a mechanism for the lack of behavioral flexibility. Front Neurosci. 2013; 7:114. PMC: 3701870. DOI: 10.3389/fnins.2013.00114. View

16.

Vargha-Khadem F, Watkins K, Price C, Ashburner J, Alcock K, Connelly A . Neural basis of an inherited speech and language disorder. Proc Natl Acad Sci U S A. 1998; 95(21):12695-700. PMC: 22893. DOI: 10.1073/pnas.95.21.12695. View

17.

Alvarez-Buylla A, Kirn J . Birth, migration, incorporation, and death of vocal control neurons in adult songbirds. J Neurobiol. 1997; 33(5):585-601. View

18.

Alm P . Stuttering and the basal ganglia circuits: a critical review of possible relations. J Commun Disord. 2004; 37(4):325-69. DOI: 10.1016/j.jcomdis.2004.03.001. View

19.

. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993; 72(6):971-83. DOI: 10.1016/0092-8674(93)90585-e. View

20.

Pouladi M, Morton A, Hayden M . Choosing an animal model for the study of Huntington's disease. Nat Rev Neurosci. 2013; 14(10):708-21. DOI: 10.1038/nrn3570. View