title: Altered glutamate release in the dorsal striatum of the MitoPark mouse model of Parkinson's disease.
abstract: Mitochondrial dysfunction has been implicated in the degeneration of dopamine (DA) neurons in Parkinson's disease (PD). In addition, animal models of PD utilizing neurotoxins, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have shown that these toxins disrupt mitochondrial respiration by targeting complex I of the electron transport chain, thereby impairing DA neurons in these models. A MitoPark mouse model was created to mimic the mitochondrial dysfunction observed in the DA system of PD patients. These mice display the same phenotypic characteristics as PD, including accelerated decline in motor function and DAergic systems with age. Previously, these mice have responded to L-Dopa treatment and develop L-Dopa induced dyskinesia (LID) as they age. A potential mechanism involved in the formation of LID is greater glutamate release into the dorsal striatum as a result of altered basal ganglia neurocircuitry due to reduced nigrostriatal DA neurotransmission. Therefore, the focus of this study was to assess various indicators of glutamate neurotransmission in the dorsal striatum of MitoPark mice at an age in which nigrostriatal DA has degenerated. At 28 weeks of age, MitoPark mice had, upon KCl stimulation, greater glutamate release in the dorsal striatum compared to control mice. In addition, uptake kinetics were slower in MitoPark mice. These findings were coupled with reduced expression of the glutamate re-uptake transporter, GLT-1, thus providing an environment suitable for glutamate excitotoxic events, leading to altered physiological function in these mice.
authors.affiliation: Department of Neuroscience and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB 403, MSC 510, Charleston, SC 29425, USA.
authors.forename: Ariana Q
authors.initials: AQ
authors.lastname: Farrand
authors.affiliation: Department of Neuroscience and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB 403, MSC 510, Charleston, SC 29425, USA; Department of Comparative Medicine, Medical University of South Carolina, 114 Doughty St, STB 648, MSC 777, Charleston, SC 29425, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Gregory
authors.affiliation: Integrative Neuroscience Section, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
authors.affiliation: Department of Comparative Medicine, Medical University of South Carolina, 114 Doughty St, STB 648, MSC 777, Charleston, SC 29425, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Helke
authors.affiliation: Department of Neuroscience and Center on Aging, Medical University of South Carolina, 173 Ashley Ave, BSB 403, MSC 510, Charleston, SC 29425, USA. Electronic address: boger@musc.edu.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Boger
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D011189:Potassium Chloride / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; C578936:Grm5 protein, mouse; D018377:Neurotransmitter Agents; D064529:Receptor, Metabotropic Glutamate 5; C528900:glial fibrillary astrocytic protein, mouse; D018698:Glutamic Acid; D011189:Potassium Chloride; D004298:Dopamine
keywords: Dopamine; Glutamate; In vivo electrochemistry; MitoPark; Neurodegeneration; Striatum