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

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Mätlik , K , Võikar , V , Vilenius , C , Kulesskaya , N & Andressoo , J-O 2018 , ' Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects ' , Scientific Reports , vol. 8 , no. 1 , 11861 . https://doi.org/10.1038/s41598-018-29988-1

Title: Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects
Author: Mätlik, Kärt; Võikar, Vootele; Vilenius, Carolina; Kulesskaya, Natalia; Andressoo, Jaan-Olle
Contributor organization: Medicum
Department of Pharmacology
University of Helsinki
Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Institute of Biotechnology
Date: 2018-08-08
Language: eng
Number of pages: 14
Belongs to series: Scientific Reports
ISSN: 2045-2322
DOI: https://doi.org/10.1038/s41598-018-29988-1
URI: http://hdl.handle.net/10138/238814
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.
Subject: 3112 Neurosciences
1182 Biochemistry, cell and molecular biology
NEUROTROPHIC-FACTOR GDNF
NIGROSTRIATAL DOPAMINE SYSTEM
AGED FISCHER-344 RATS
PARKINSONS-DISEASE
TYROSINE-HYDROXYLASE
IN-VIVO
MESOLIMBIC DOPAMINE
PREPULSE INHIBITION
AGGRESSIVE-BEHAVIOR
LOCOMOTOR-ACTIVITY
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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