GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice

Cui Liu; Wen-Hong Liu; Wu Yang; Lei Chen; Yan Xue; Xin-Yi Chen

doi:10.1016/j.neuropharm.2024.109946

GLP-1 modulated the firing activity of nigral dopaminergic neurons in both normal and parkinsonian mice

Neuropharmacology. 2024 Apr 9:252:109946. doi: 10.1016/j.neuropharm.2024.109946. Online ahead of print.

Authors

Cui Liu¹, Wen-Hong Liu², Wu Yang³, Lei Chen², Yan Xue², Xin-Yi Chen⁴

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China; Department of Histology and Embryology, School of Clinical and Basic Medical Sciences, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
² Department of Physiology and Pathophysiology, School of Basic Medicine, Qingdao University, Qingdao, China.
³ Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China.
⁴ Department of International Medicine, Affiliated Hospital of Qingdao University, Qingdao, China. Electronic address: caroline_cross@163.com.

PMID: 38599494
DOI: 10.1016/j.neuropharm.2024.109946

Abstract

The spontaneous firing activity of nigral dopaminergic neurons is associated with some important roles including modulation of dopamine release, expression of tyrosine hydroxylase (TH), as well as neuronal survival. The decreased neuroactivity of nigral dopaminergic neurons has been revealed in Parkinson's disease. Central glucagon-like peptide-1 (GLP-1) functions as a neurotransmitter or neuromodulator to exert multiple brain functions. Although morphological studies revealed the expression of GLP-1 receptors (GLP-1Rs) in the substantia nigra pars compacta, the possible modulation of GLP-1 on spontaneous firing activity of nigral dopaminergic neurons is unknown. The present extracellular in vivo single unit recordings revealed that GLP-1R agonist exendin-4 significantly increased the spontaneous firing rate and decreased the firing regularity of partial nigral dopaminergic neurons of adult male C57BL/6 mice. Blockade of GLP-1Rs by exendin (9-39) decreased the firing rate of nigral dopaminergic neurons suggesting the involvement of endogenous GLP-1 in the modulation of firing activity. Furthermore, the PKA and the transient receptor potential canonical (TRPC) 4/5 channels are involved in activation of GLP-1Rs-induced excitatory effects of nigral dopaminergic neurons. Under parkinsonian state, both the exogenous and endogenous GLP-1 could still induce excitatory effects on the surviving nigral dopaminergic neurons. As the mild excitatory stimuli exert neuroprotective effects on nigral dopaminergic neurons, the present GLP-1-induced excitatory effects may partially contribute to its antiparkinsonian effects.

Keywords: Dopaminergic neuron; Firing activity; GLP-1; Parkinson's disease; Substantia nigra pars compacta.