Objective: Although reactive gliosis is a prominent feature of PD, its role in pathogenesis has remained elusive. Here we show that aberrantly synthesized GABA from reactive astrocytes tonically inhibits neighboring dopaminergic neuronal firing in SNpc, reducing dopamine production and release, leading to parkinsonian motor symptoms.

Background: Parkinsonism is a clinical syndrome of movement abnormalities seen in Parkinson’s disease (PD), which has been attributed to cell-autonomous mechanism of doparminergic neuronal death in the substantia nigra pars compacta (SNpc).

Methods: To identify the GABA from reactive astrocyte in PD, we used toxin induced model (MPP+, 6-OHDA rat model, MPTP mouse model) and overexpressed alpha synuclein mouse model. Moreover, we also assessed it in postmortem PD patients’ brain.

Results: The released GABA from astrocyte tonically inhibits pacemaker action potential firing of neighboring DA neurons, resulting in reduced tyrosine hydroxylase expression and Parkinson-like motor symptoms. Impairments are fully restored by treatment with the MAO-B inhibitor, selegiline. The effects of glial GABA and selegiline were mimicked by optogenetic silencing and activation of DA firing, respectively. Brain samples of PD patients revealed a plethora of GABA-positive reactive astrocytes with a significantly increased MAO-B mRNA expression.

Conclusions: Our study proposes that glial GABA is inextricably linked to parkinsonism, which can arise even before substantial dopaminergic neuronal death.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsonism-through-astrocytic-gaba-induce-motor-symptoms/