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bioRxiv · 10.1101/2021.02.15.431290

Nicotine-mediated recruitment of GABAergic neurons to a dopaminergic phenotype attenuates motor deficits in alpha-synuclein Parkinson's model.

Lai, I.-C.·Romoli, B.·Keisler, M.·Manfredsson, F.·Powell, S. B.·Dulcis, D.
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Abstract

BACKGROUNDPrevious work revealed an inverse correlation between smoking and Parkinsons disease (PD) that is associated with nicotine-induced neuroprotection of dopaminergic (DA) neurons against nigrostriatal damage in PD primates and rodent models. Nicotine, a neuroactive component of tobacco, can directly alter the activity of midbrain DA neurons and induce non-DA neurons in the substantia nigra (SN) to acquire a DA phenotype. We investigated the recruitment mechanism of nigrostriatal GABAergic neurons to express DA phenotypes, such as transcription factor Nurr1 and DA-synthesizing enzyme tyrosine hydroxylase (TH), and the concomitant effects on motor function. METHODSWild-type and -syn-overexpressing (PD) mice treated with chronic nicotine were assessed by behavioral pattern monitor (BPM) and immunohistochemistry/in-situ hybridization to measure behavior and the translational/transcriptional regulation of neurotransmitter phenotype following selective Nurr1 overexpression or DREADD-mediated chemogenetic activation. RESULTSNicotine treatment led to a transcriptional TH and translational Nurr1 upregulation within a pool of SN GABAergic neurons in wild-type animals. In PD mice, nicotine increased Nurr1 expression, reduced the number of -syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1 in non-DA neurons. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. CONCLUSIONSNicotine exposure initiates neuroprotective mechanisms counteracting the neurodegenerative effects of -syn accumulation in DA neurons and contributing to Nurr1-mediated therapeutic effects. Revealing the mechanism of nicotine-induced DA plasticity protecting SN neurons against nigrostriatal damage could contribute to developing new strategies for neurotransmitter replacement in PD.

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Lai, I.-C., Romoli, B., Keisler, M., Manfredsson, F., Powell, S. B., Dulcis, D.. 2021-02-16. Nicotine-mediated recruitment of GABAergic neurons to a dopaminergic phenotype attenuates motor deficits in alpha-synuclein Parkinson's model.. https://doi.org/10.1101/2021.02.15.431290

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