Deletion of the Creatine Transporter ( Slc6a8 ) in Dopaminergic Neurons Leads to Hyperactivity in Mice
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Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice Zuhair I. Abdulla 1,3 & Bahar Pahlevani 1 & Kerstin H. Lundgren 2 & Jordan L. Pennington 1 & Kenea C. Udobi 1,3 & Kim B. Seroogy 2,3 & Matthew R. Skelton 1,3 Received: 30 July 2019 / Accepted: 30 August 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract The lack of cerebral creatine (Cr) causes intellectual disability and epilepsy. In addition, a significant portion of individuals with Cr transporter (Crt) deficiency (CTD), the leading cause of cerebral Cr deficiency syndromes (CCDS), are diagnosed with attention-deficit hyperactivity disorder. While the neurological effects of CTD are clear, the mechanisms that underlie these deficits are unknown. Part of this is due to the heterogenous nature of the brain and the unique metabolic demands of specific neuronal systems. Of particular interest related to Cr physiology are dopaminergic neurons, as many CCDS patients have ADHD and Cr has been implicated in dopamine-associated neurodegenerative disorders, such as Parkinson’s and Huntington’s diseases. The purpose of this study was to examine the effect of a loss of the Slc6a8 (Crt) gene in dopamine transporter (Slc6a3; DAT) expressing cells on locomotor activity and motor function as the mice age. Floxed Slc6a8 (Slc6a8flox) mice were mated to DATIREScre expressing mice to generate DAT-specific Slc6a8 knockouts (dCrt−/y). Locomotor activity, spontaneous activity, and performance in the challenging beam test were evaluated monthly in dCrt−/y and control (Slc6a8flox) mice from 3 to 12 months of age. dCrt−/y mice were hyperactive compared with controls throughout testing. In addition, dCrt−/y mice showed increased rearing and hindlimb steps in the spontaneous activity test. Latency to cross the narrow bridge was increased in dCrt−/y mice while foot slips were unchanged. Taken together, these data suggest that the lack of Cr in dopaminergic neurons causes hyperactivity while sparing motor function. Keywords Creatine . Creatine transporter . DAT-Cre . Hyperactivity . Motor function
Introduction Creatine (Cr) is a nitrogenous acid involved in energy homeostasis. Through a Cr kinase (CK)-mediated process, Cr is phosphorylated at sites of energy production and diffuses through the cytosol, creating phospho-Cr (PCr) pools (Wallimann et al. 2011, Lowe et al. 2013). At sites of ATP consumption, CK transfers the phosphate from PCr to ADP (Wyss and Kaddurah-Daouk 2000). The Cr/PCr shuttle is a
* Matthew R. Skelton [email protected] 1
Department of Pediatrics, University of Cincinnati College of Medicine and Division of Neurology, Cincinnati Children’s Research Foundation, Cincinnati, OH, USA
2
Department of Neurology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
3
Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH, USA
spatial and temporal ATP buffer, preventing transient changes in ATP:ADP or ATP:AMP ratios from increasing mitochondrial produc
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