Unraveling the Mechanisms Underlying Irregularities in Inspiratory Rhythm Generation in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder anatomically characterized by a progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Much less known, yet clinically very important, are the detrimental effects on breathing associated with this disease. Consistent with the human pathophysiology, the 6-hydroxydopamine hydrochloride (6-OHDA) rodent model of PD shows reduced respiratory frequency (f(R)) and NK1r-immunoreactivity in the pre-Botzinger complex (preBotC) and PHOX2B(+) neurons in the retrotrapezoid nucleus (RTN). To unravel mechanisms that underlie bra-dypnea in PD, we employed a transgenic approach to label or stimulate specific neuron populations in various respiratory-related brainstem regions. PD mice were characterized by a pronounced decreased number of putatively rhythmically active excitatory neurons in the preBotC and adjacent ventral respiratory column (VRC). Specifically, the number of Dbx1 and Vglut(2) neurons was reduced by 47.6% and 17.3%, respectively. By contrast, inhibitory Vgat(+) neurons in the VRC, as well as neurons in other respiratory-related brainstem regions, showed relatively minimal or no signs of neuronal loss. Consistent with these anatomic observations, optogenetic experiments identified deficits in respiratory function that were specific to manipulations of excitatory (Dbx1/Vglut(2)) neurons in the preBotC. We conclude that the decreased number of this critical population of respiratory neurons is an important contributor to the development of irregularities in inspiratory rhythm generation in this mouse model of PD.

Automated summary

Parkinson's disease leads to breathing abnormalities, with the 6-OHDA rodent model showing reduced respiratory frequency associated with PD. PD mice exhibit a decreased number of critical respiratory neurons, resulting in respiratory deficits specific to inspiratory rhythm generation.