title: Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice.
abstract: The prevailing circuit model predicts that hyperactivity of the striatopallidal pathway and subsequently increased inhibition of external globus pallidus (GPe) neurons lead to the hypokinetic symptoms of Parkinson's disease (PD). It is believed that hyperactivity of the striatopallidal pathway is due to inactivity of dopamine receptors on the somatodendritic membrane of striatopallidal neurons, but the exact cellular underpinnings remain unclear. In this study, we show that mouse GPe astrocytes critically control ambient glutamate level, which in turn gates striatopallidal transmission via the activation of presynaptic metabotropic glutamate receptors. This presynaptic inhibition of striatopallidal transmission is diminished after the chronic loss of dopamine. Elevation of intracellular glutamate content in astrocytes restores the proper regulation of the striatopallidal input in PD models. These findings argue that astrocytes are key regulators of the striatopallidal synapse. Targeting this cell class may serve as an alternative therapeutic strategy for PD.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Pitt
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Arin
authors.initials: A
authors.lastname: Pamukcu
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Poulin
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Mabrouk
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fiske
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Isabel B
authors.initials: IB
authors.lastname: Fan
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Augustine
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Young
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Kennedy
authors.affiliation: Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Awatramani
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: saviochan@gmail.com.
authors.forename: C Savio
authors.initials: CS
authors.lastname: Chan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004298:Dopamine / Q000494:pharmacology; D005917:Globus Pallidus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine
keywords: 6-OHDA; GCaMP; astrocytes; basal ganglia; external globus pallidus; glutamate homeostasis; iGluSnFR; patch-clamp; striatum; tyrosine hydroxylase