Nicotine-Mediated Recruitment of GABAergic Neurons to a Dopaminergic Phenotype Attenuates Motor Deficits in an Alpha-Synuclein Parkinson’s Model

Abstract

Previous work revealed an inverse correlation between tobacco smoking and Parkinson’s 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. Here, 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. Wild-type and α-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. We found that nicotine 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 α-syn-expressing neurons, and simultaneously rescued motor deficits. Hyperactivation of GABA neurons alone was sufficient to elicit de novo translational upregulation of Nurr1. Retrograde labeling revealed that a fraction of these GABAergic neurons projects to the dorsal striatum. Finally, concomitant depolarization and Nurr1 overexpression within GABA neurons were sufficient to mimic nicotine-mediated dopamine plasticity. 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.

Salidroside Mediated the Nrf2/GPX4 Pathway to Attenuates Ferroptosis in Parkinson’s Disease

“…In addition, TH, a rate-limiting enzyme in dopamine synthesis, typically shows decreased expression in PD [ 38 ], serving as a marker for the loss of dopaminergic neurons. In parallel, we observed that elevated levels of α-synuclein, a protein implicated in PD pathogenesis due to its tendency to form toxic aggregates [ 39 ], were significantly reduced following SAL treatment. This dual modulation of TH and α-synuclein by SAL highlights its potential as a targeted therapeutic strategy against the core pathological features of PD [ 40 ].…”

Nicotinic Acetylcholine Receptors in Glial Cells as Molecular Target for Parkinson’s Disease

“…Moreover, using D-line α-Syn transgenic mice, and a humanized neuronal model of synucleinopathies, it was revealed that nicotine via activation of α4β2 nicotinic receptors attenuates α-Syn-provoked neuropathology [194]. In a similar in-vivo study, it was shown that nicotine attenuates motor deficits in an α-Syn PD model [195]. Thus, manipulating both α4β2 and α7nAChRs may effectively mitigate synucleinopathies [178,194,196].…”

Bioelectronic Medicine: a multidisciplinary roadmap from biophysics to precision therapies

“…Activity induced-changes in neurotransmitter identity can substantially impact the ability of the individual to deal with the environment, by promoting either advantageous or disadvantageous changes in behavior. Beneficial effects have been linked to changes in the transmitter identity of midbrain neurons and could pave the way for novel treatment opportunities in motor and neurodegenerative disorders ( Table 1 ; Steinkellner et al, 2018 , 2022 ; Li and Spitzer, 2020 ; Lai et al, 2023 ). In contrast, changes in the neurotransmitter phenotype of hypothalamic neurons cause stress-induced behaviors in response to seasonal changes in photoperiod length ( Dulcis et al, 2013 ; Porcu et al, 2022 ).…”

“…These promote the development and use of quantitative resources to understand brain circuits from cellular to behavioral scales and across multiple species. Some outcomes include progress in the neuromodulation of the spinal cord for motor recovery after stroke (Powell et al, 2023), DBS personalization in the treatment of resistant depression, and the identification of neuronal signatures predicting pain in the brain of patients with chronic pain, by the use of intracranial electrodes (Shirvalkar et al, 2023). This is a continuously growing field, which demands the integration of multiple disciplines, and has led to the creation of consortiums for data management to understand the nervous system.…”