UC San Diego
Nicotine-induced Neurotransmitter Plasticity in the Substantia Nigra: Implications for Parkinson’s Disease
- Author(s): Lai, I-Chi
- Advisor(s): Dulcis, Davide
- Berg, Darwin
- et al.
Cigarette smoking is generally known for its detrimental effects on health; however, extensive epidemiological studies have indicated inverse correlation between smoking and Parkinson’s Disease (PD), a progressive neurodegenerative disorder characterized by loss of dopaminergic (DAergic) neurons in the substantia nigra (SN). Subsequent studies have shown that nicotine protects DAergic neurons against nigrostriatal damage in PD primate and rodent models. Nicotine became the focus of these studies due to its well-known ability to modulate function and activity of midbrain DAergic neurons. Because altered circuit activation can induce neurons to acquire a DAergic phenotype in the mature brain, we hypothesized that chronic nicotine treatment contributes to neuroprotection against nigrostriatal damage in an animal model of PD via a mechanism of neurotransmitter plasticity.
Nicotine was given to adult mice in drinking water for two weeks. Brains of various transgenic reporter mouse lines were subsequently processed for immunohistochemistry and retrobead tracing for detection of tyrosine hydroxylase and other cell markers in the SN, and neuronal connectivity. Selective overexpression of human A53T alpha synuclein in midbrain DAergic neurons was used as a PD mouse model.
Our findings showed that chronic nicotine treatment significantly increased DA expression within a pool of SNr (pars reticulata) GABAergic neurons that express transcription factors associated with DA differentiation, such as Nurr1 and Foxa2, prior to nicotine exposure. More importantly, our retrograde labelling experiments showed that this GABAergic neuronal pool in the SNr projects to the caudate nucleus, the same target of SNc (pars compacta) DAergic neurons. Ongoing behavioral experiments on a PD mouse model confirmed that nicotine treatment ameliorates some motor deficits in these mice. Our results indicate that neurotransmitter plasticity occurs in the SN in response to chronic nicotine treatment. Understanding its role in neuroprotection against nigrostriatal damages in PD could reveal insights that may lead to the development of new treatments for Parkinson’s Disease.