Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects

Abstract Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopaminergic neurons in vitro and in vivo. For this reason, GDNF is currently in clinical trials for the treatment of Parkinson’s disease (PD). However, how endogenous GDNF influences dopamine system function and an...

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Autores principales:	Kärt Mätlik, Vootele Võikar, Carolina Vilenius, Natalia Kulesskaya, Jaan-Olle Andressoo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4c8060365899450983ac1b9eea80ab2e
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spelling	oai:doaj.org-article:4c8060365899450983ac1b9eea80ab2e2021-12-02T15:09:11ZTwo-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects10.1038/s41598-018-29988-12045-2322https://doaj.org/article/4c8060365899450983ac1b9eea80ab2e2018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-29988-1https://doaj.org/toc/2045-2322Abstract Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopaminergic neurons in vitro and in vivo. For this reason, GDNF is currently in clinical trials for the treatment of Parkinson’s disease (PD). However, how endogenous GDNF influences dopamine system function and animal behavior is not fully understood. We recently generated GDNF hypermorphic mice that express increased levels of endogenous GDNF from the native locus, resulting in augmented function of the nigrostriatal dopamine system. Specifically, Gdnf wt/hyper mice have a mild increase in striatal and midbrain dopamine levels, increased dopamine transporter activity, and 15% increased numbers of midbrain dopamine neurons and striatal dopaminergic varicosities. Since changes in the dopamine system are implicated in several neuropsychiatric diseases, including schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, and ectopic GDNF delivery associates with side-effects in PD models and clinical trials, we further investigated Gdnf wt/hyper mice using 20 behavioral tests. Despite increased dopamine levels, dopamine release and dopamine transporter activity, there were no differences in psychiatric disease related phenotypes. However, compared to controls, male Gdnf wt/hyper mice performed better in tests measuring motor function. Therefore, a modest elevation of endogenous GDNF levels improves motor function but does not induce adverse behavioral outcomes.Kärt MätlikVootele VõikarCarolina VileniusNatalia KulesskayaJaan-Olle AndressooNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kärt Mätlik Vootele Võikar Carolina Vilenius Natalia Kulesskaya Jaan-Olle Andressoo Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
description	Abstract Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopaminergic neurons in vitro and in vivo. For this reason, GDNF is currently in clinical trials for the treatment of Parkinson’s disease (PD). However, how endogenous GDNF influences dopamine system function and animal behavior is not fully understood. We recently generated GDNF hypermorphic mice that express increased levels of endogenous GDNF from the native locus, resulting in augmented function of the nigrostriatal dopamine system. Specifically, Gdnf wt/hyper mice have a mild increase in striatal and midbrain dopamine levels, increased dopamine transporter activity, and 15% increased numbers of midbrain dopamine neurons and striatal dopaminergic varicosities. Since changes in the dopamine system are implicated in several neuropsychiatric diseases, including schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, and ectopic GDNF delivery associates with side-effects in PD models and clinical trials, we further investigated Gdnf wt/hyper mice using 20 behavioral tests. Despite increased dopamine levels, dopamine release and dopamine transporter activity, there were no differences in psychiatric disease related phenotypes. However, compared to controls, male Gdnf wt/hyper mice performed better in tests measuring motor function. Therefore, a modest elevation of endogenous GDNF levels improves motor function but does not induce adverse behavioral outcomes.
format	article
author	Kärt Mätlik Vootele Võikar Carolina Vilenius Natalia Kulesskaya Jaan-Olle Andressoo
author_facet	Kärt Mätlik Vootele Võikar Carolina Vilenius Natalia Kulesskaya Jaan-Olle Andressoo
author_sort	Kärt Mätlik
title	Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
title_short	Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
title_full	Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
title_fullStr	Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
title_full_unstemmed	Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
title_sort	two-fold elevation of endogenous gdnf levels in mice improves motor coordination without causing side-effects
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/4c8060365899450983ac1b9eea80ab2e
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Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects

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