Orexins alleviate motor deficits via increasing firing activity of pallidal neurons in a mouse model of Parkinson’s disease

Abstract

Orexin is a peptide neurotransmitter released in the globus pallidus. Morphological evidence reveals that both orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R) exist in the globus pallidus. Here we showed that bilateral microinjection of both orexin-A and orexin-B into the globus pallidus alleviated motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian mice. Further in vivo extracellular single-unit recording revealed that the basal spontaneous firing rate of the globus pallidus neurons in MPTP parkinsonian mice was slower than that of normal mice. Application of orexin-A or orexin-B significantly increased the spontaneous firing rate of pallidal neurons. The influx of Ca2+ through the L-type Ca2+ channel is the major mechanism involved in orexin-induced excitation in the globus pallidus. Orexin-A-induced increase in firing rate of pallidal neurons in MPTP parkinsonian mice was stronger than that of normal mice. Orexin-A exerted both electrophysiological and behavioral effects mainly via OX1R, and orexin-B exerted the effects via OX2R. Endogenous orexins modulated the excitability of globus pallidus neurons mainly through OX1R. The present behavioral and electrophysiological results suggest that orexins ameliorate parkinsonian motor deficits through increasing the spontaneous firing of globus pallidus neurons.

The role of orexin in Parkinson's disease

“…There was no specific time point given in this study as to when orexin neuron loss was measured as the protocol timeframe varied (Fifel et al., 2014). In an MPTP PD model in mice, no orexin loss was also found when compared to controls; however, there was no timeline as to when orexin neurons loss was measured (Wang et al., 2019). From 6‐OHDA studies, it appears that orexin neuron loss occurs at later stages (after 40–60 days); therefore, the MPTP animal models may need to be repeated with longer timeframes.…”

“…In a recent study on MPTP‐induced mice, the mice exhibited motor deficits and the intracerebroventricular (ICV) administration of orexin B increased general spontaneous activity and alleviated motor coordination deficits (Bian et al., 2021). Another study on MPTP PD‐induced mice found that motor deficits were reversed and pallidal neuron (which are involved in regulating proprioceptive and conscious movement) spontaneous firing rates were increased with the injection of orexin A and orexin B into the globus pallidus (Wang et al., 2019). Consistently, in MPTP PD‐induced mice, the administration of orexin A reversed motor deficits shown by significantly reducing the t‐turn time (time to turn downward from the top of the pole) in the pole test and significantly increasing the total distance traveled in the open field test (Liu et al., 2018).…”

International Union of Basic and Clinical Pharmacology CXIV: Orexin Receptor Function, Nomenclature and Pharmacology

“…Different mechanisms such as induction of hypoxia-induced factor-1 (Yuan et al, 2011), reduced inflammation (Xiong et al, 2013), inhibition of endoplasmic reticulum stress (Xu et al, 2021) and inhibition of autophagy (Zhang et al, 2022) (Guerreiro et al, 2015;Liu et al, 2018b), though there are still confounding factors in these. One such study reports a functional motor improvement by exogenous orexins in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -induced PD mouse model (Wang et al, 2019b).…”

Focus on the Complex Interconnection between Cancer, Narcolepsy and Other Neurodegenerative Diseases: A Possible Case of Orexin-Dependent Inverse Comorbidity

“…At least in part, this effect may result from enhanced sleep-related brain glymphatic clearance of metabolic by-products, such as amyloid-β [ 159 , 160 ]. On the other hand, studies on mouse models show that orexins can ameliorate parkinsonian motor deficits by increasing the spontaneous activation of pallidal neurons [ 161 ].…”