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Cell Rep. 2016 Nov 22;17(9):2431-2444. doi: 10.1016/j.celrep.2016.10.087.

Blunted mGluR Activation Disinhibits Striatopallidal Transmission in Parkinsonian Mice.

Author information

1
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
2
Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
3
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: saviochan@gmail.com.

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.

KEYWORDS:

6-OHDA; GCaMP; astrocytes; basal ganglia; external globus pallidus; glutamate homeostasis; iGluSnFR; patch-clamp; striatum; tyrosine hydroxylase

PMID:
27880915
PMCID:
PMC5489133
DOI:
10.1016/j.celrep.2016.10.087
[Indexed for MEDLINE]
Free PMC Article

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