Enhanced firing of locus coeruleus neurons and SK channel dysfunction are conserved in distinct models of prodromal Parkinson's disease.

Autor: Matschke LA; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany.; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany., Komadowski MA; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany., Stöhr A; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany., Lee B; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany., Henrich MT; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany., Griesbach M; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany., Rinné S; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany., Geibl FF; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany., Chiu WH; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany., Koprich JB; Krembil Research Institute, Toronto Western Hospital, University Health Network, 8KD402, Toronto, ON, M5T 2S8, Canada., Brotchie JM; Krembil Research Institute, Toronto Western Hospital, University Health Network, 8KD402, Toronto, ON, M5T 2S8, Canada., Kiper AK; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany., Dolga AM; Faculty of Science and Engineering, Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, 9713 AV, Groningen, The Netherlands., Oertel WH; Clinic for Neurology, Philipps-University Marburg, 35043, Marburg, Germany.; Hertie Senior Research Professor of the Charitable Hertie Foundation, 60323, Frankfurt am Main, Germany., Decher N; Institute for Physiology and Pathophysiology, Vegetative Physiology and Marburg Center for Mind, Brain and Behavior - MCMBB, Philipps-University Marburg, 35037, Marburg, Germany. decher@staff.uni-marburg.de.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Feb 24; Vol. 12 (1), pp. 3180. Date of Electronic Publication: 2022 Feb 24.
DOI: 10.1038/s41598-022-06832-1
Abstrakt: Parkinson's disease (PD) is clinically defined by the presence of the cardinal motor symptoms, which are associated with a loss of dopaminergic nigrostriatal neurons in the substantia nigra pars compacta (SNpc). While SNpc neurons serve as the prototypical cell-type to study cellular vulnerability in PD, there is an unmet need to extent our efforts to other neurons at risk. The noradrenergic locus coeruleus (LC) represents one of the first brain structures affected in Parkinson's disease (PD) and plays not only a crucial role for the evolving non-motor symptomatology, but it is also believed to contribute to disease progression by efferent noradrenergic deficiency. Therefore, we sought to characterize the electrophysiological properties of LC neurons in two distinct PD models: (1) in an in vivo mouse model of focal α-synuclein overexpression; and (2) in an in vitro rotenone-induced PD model. Despite the fundamental differences of these two PD models, α-synuclein overexpression as well as rotenone exposure led to an accelerated autonomous pacemaker frequency of LC neurons, accompanied by severe alterations of the afterhyperpolarization amplitude. On the mechanistic side, we suggest that Ca 2+ -activated K + (SK) channels are mediators of the increased LC neuronal excitability, as pharmacological activation of these channels is sufficient to prevent increased LC pacemaking and subsequent neuronal loss in the LC following in vitro rotenone exposure. These findings suggest a role of SK channels in PD by linking α-synuclein- and rotenone-induced changes in LC firing rate to SK channel dysfunction.
(© 2022. The Author(s).)
Databáze: MEDLINE
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