Deletion of the Creatine Transporter (Slc6a8) in Dopaminergic Neurons Leads to Hyperactivity in Mice
- 50 Downloads
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.
KeywordsCreatine Creatine transporter DAT-Cre Hyperactivity Motor function
The authors would like to thank Marla K. Perna and Keila N. Miles for providing scientific input and proofreading this article.
Mr. Abdulla, Dr. Seroogy, and Dr. Skelton designed the experiment and drafted and edited the manuscript. Mr. Abdulla, Ms. Pahlevani, Ms. Lundgren, Ms. Pennington, and Mr. Udobi conducted and scored all experiments.
This work was supported by National Institutes of Health grant HD080910 and a CARE grant from the Association of Creatine Deficiencies. Portions were supported by the Kerman Family Fund, the Selma Schottenstein Harris Lab for Research in Parkinson’s, the Gardner Family Center for Parkinson’s Disease and Movement Disorders, and the Parkinson’s Disease Support Network, Ohio, Kentucky, and Indiana.
- Abdulla, Z. I., J. L. Pennington, A. Gutierrez and M. R. Skelton (2019). “Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness.” bioRxiv: 641845Google Scholar
- Birgner C, Nordenankar K, Lundblad M, Mendez JA, Smith C, le Greves M, Galter D, Olson L, Fredriksson A, Trudeau LE, Kullander K, Wallen-Mackenzie A (2010) VGLUT2 in dopamine neurons is required for psychostimulant-induced behavioral activation. Proc Natl Acad Sci U S A 107(1):389–394CrossRefGoogle Scholar
- Cunha MP, Martin-de-Saavedra MD, Romero A, Parada E, Egea J, Del Barrio L, Rodrigues AL, Lopez MG (2013) Protective effect of creatine against 6-hydroxydopamine-induced cell death in human neuroblastoma SH-SY5Y cells: involvement of intracellular signaling pathways. Neuroscience 238:185–194CrossRefGoogle Scholar
- Fleming SM, (2004) Early and Progressive Sensorimotor Anomalies in Mice Overexpressing Wild-Type Human -Synuclein. J. Neurosci 24 (42):9434-9440Google Scholar
- Gomez-Lazaro M, Galindo MF, Concannon CG, Segura MF, Fernandez-Gomez FJ, Llecha N, Comella JX, Prehn JH, Jordan J (2008) 6-Hydroxydopamine activates the mitochondrial apoptosis pathway through p38 MAPK-mediated, p53-independent activation of Bax and PUMA. J Neurochem 104(6):1599–1612CrossRefGoogle Scholar
- Hemmerle AM, Dickerson JW, Herring NR, Schaefer TL, Vorhees CV, Williams MT, Seroogy KB (2012) (+/−)3,4-methylenedioxymethamphetamine (“ecstasy”) treatment modulates expression of neurotrophins and their receptors in multiple regions of adult rat brain. J Comp Neurol 520(11):2459–2474CrossRefGoogle Scholar
- Hosamani, R., S. R. Ramesh and Muralidhara (2010). “Attenuation of rotenone-induced mitochondrial oxidative damage and neurotoxicty in Drosophila melanogaster supplemented with creatine.” Neurochem Res 35(9): 1402–1412Google Scholar
- Kostrzewa, J. P., Kostrzewa, R. A., Kostrzewa, R. M., Brus, R., & Nowak, P. (2015). Perinatal 6-Hydroxydopamine Modeling of ADHD. Curr Top Behav Neurosci. doi:10.1007/7854_2015_397Google Scholar
- O’neil B, Gu HH (2013) Amphetamine-induced locomotion in a hyperdopaminergic ADHD mouse model depends on genetic background. Pharmacol Biochem Behav 103 (3):455–459Google Scholar
- Pinto M, Nissanka N, Peralta S, Brambilla R, Diaz F, Moraes CT (2016) Pioglitazone ameliorates the phenotype of a novel Parkinson’s disease mouse model by reducing neuroinflammation. Mol. Neurodegener 11 (1). https://doi.org/10.1186/s13024-016-0090-7
- Runegaard AH, Sorensen AT, Fitzpatrick CM, Jorgensen SH, Petersen AV, Hansen NW, Weikop P, Andreasen JT, Mikkelsen JD, Perrier JF, Woldbye D, Rickhag M, Wortwein G, Gether U (2018) Locomotor- and reward-enhancing effects of cocaine are differentially regulated by chemogenetic stimulation of Gi-signaling in dopaminergic neurons. eNeuro 5(3):ENEURO.0345–ENEU17.2018CrossRefGoogle Scholar
- Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST (2000) CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39 (5):777–787Google Scholar
- Seroogy KB, Herman JP (1997) In situ hybridization approaches to the study of the nervous system. In: Turner AJ, Bachelard HS (eds) Neurochemistry: a practical approach (2nd edition). Oxford University Press, Oxford, pp 121–150Google Scholar
- Udobi, K. C., N. Delcimmuto, A. N. Kokenge, Z. I. Abdulla, M. K. Perna and M. R. Skelton (2019). “Deletion of the creatine transporter gene in neonatal, but not adult, mice lead to cognitive deficits.” bioRxiv: 582320Google Scholar
- van de Kamp JM, Betsalel OT, Mercimek-Mahmutoglu S, Abulhoul L, Grunewald S, Anselm I, Azzouz H, Bratkovic D, de Brouwer A, Hamel B, Kleefstra T, Yntema H, Campistol J, Vilaseca MA, Cheillan D, D'Hooghe M, Diogo L, Garcia P, Valongo C, Fonseca M, Frints S, Wilcken B, von der Haar S, Meijers-Heijboer HE, Hofstede F, Johnson D, Kant SG, Lion-Francois L, Pitelet G, Longo N, Maat-Kievit JA, Monteiro JP, Munnich A, Muntau AC, Nassogne MC, Osaka H, Ounap K, Pinard JM, Quijano-Roy S, Poggenburg I, Poplawski N, Abdul-Rahman O, Ribes A, Arias A, Yaplito-Lee J, Schulze A, Schwartz CE, Schwenger S, Soares G, Sznajer Y, Valayannopoulos V, Van Esch H, Waltz S, Wamelink MM, Pouwels PJ, Errami A, van der Knaap MS, Jakobs C, Mancini GM, Salomons GS (2013) Phenotype and genotype in 101 males with X-linked creatine transporter deficiency. J Med Genet 50(7):463–472CrossRefGoogle Scholar
- Xiong N, Long X, Xiong J, Jia M, Chen C, Huang J, Ghoorah D, Kong X, Lin Z, Wang T (2012) Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Crit Rev Toxicol 42(7):613–632Google Scholar