Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guampopulation. β-N-Methylamino alanine(BMAA)has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca2+] i ) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca2+]i in DAergic neurons. The inward current (IBMAA) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced IBMAA, and a small component of IBMAA was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD. Copyright © 2010 the authors.

Cucchiaroni, M. L., Viscomi, M. T., Bernardi, G., Molinari, M., Guatteo, E., Mercuri, N. B., Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative β-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons, <<THE JOURNAL OF NEUROSCIENCE>>, 2010; 30 (15): 5176-5188. [doi:10.1523/JNEUROSCI.5351-09.2010] [http://hdl.handle.net/10807/198242]

Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative β-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons

Viscomi, Maria Teresa
Supervision
;
2010

Abstract

Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, and Alzheimer's symptoms that is prevalent in the Guampopulation. β-N-Methylamino alanine(BMAA)has been proposed as the toxic agent damaging several neuronal types in ALS-PDC, including substantia nigra pars compacta dopaminergic (SNpc DAergic) neurons. BMAA is a mixed glutamate receptor agonist, but the specific pathways activated in DAergic neurons are not yet known. We combined electrophysiology, microfluorometry, and confocal microscopy analysis to monitor membrane potential/current, cytosolic calcium concentration ([Ca2+] i ) changes, cytochrome-c (cyt-c) immunoreactivity, and reactive oxygen species (ROS) production induced by BMAA. Rapid toxin applications caused reversible membrane depolarization/inward current and increase of firing rate and [Ca2+]i in DAergic neurons. The inward current (IBMAA) was mainly mediated by activation of metabotropic glutamate receptor 1 (mGluR1), coupled to transient receptor potential (TRP) channels, and to a lesser extent, AMPA receptors. Indeed, mGluR1 (CPCCOEt) and TRP channels (SKF 96365; Ruthenium Red) antagonists reduced IBMAA, and a small component of IBMAA was reduced by the AMPA receptor antagonist CNQX. Calcium accumulation was mediated by mGluR1 but not by AMPA receptors. Application of a low concentration of NMDA potentiated the BMAA-mediated calcium increase. Prolonged exposure to BMAA caused significant modifications of membrane properties, calcium overload, cell shrinkage, massive cyt-c release into the cytosol and ROS production. In SNpc GABAergic neurons, BMAA activated only AMPA receptors. Our study identifies the mGluR1-activated mechanism induced by BMAA that may cause the neuronal degeneration and parkinsonian symptoms seen in ALS-PDC. Moreover, environmental exposure to BMAA might possibly also contribute to idiopathic PD. Copyright © 2010 the authors.
2010
Inglese
Cucchiaroni, M. L., Viscomi, M. T., Bernardi, G., Molinari, M., Guatteo, E., Mercuri, N. B., Metabotropic glutamate receptor 1 mediates the electrophysiological and toxic actions of the cycad derivative β-N-Methylamino-L-alanine on substantia nigra pars compacta DAergic neurons, <<THE JOURNAL OF NEUROSCIENCE>>, 2010; 30 (15): 5176-5188. [doi:10.1523/JNEUROSCI.5351-09.2010] [http://hdl.handle.net/10807/198242]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/198242
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