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

Abstract

Amyotrophic lateral sclerosis-Parkinson dementia complex (ALS-PDC) is a neurodegenerative disease with ALS, parkinsonism, andAlzheimer's symptoms that is prevalent in the Guam population. ␤-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 (

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

“…These studies conflict with ours; our results, showing AMPA receptor activation, suggest that neuronal responses to D-Asp may depend on the receptor isoform expressed on each cell type. In support of this, we previously showed that another natural amino-acid, b-Nmethylamino-L-alanine (BMAA) activates different glutamate receptors in different brain areas: BMAA activates metabotropic/ AMPA receptors in nigral DAergic neurons (Cucchiaroni et al, 2010), NMDA receptors in cortical neurons (Lobner et al, 2007;Weiss et al, 1989) and AMPA/kainate receptors in spinal motoneurons (Rao et al, 2006).…”

“…By means of this technique, absolute current amplitude and kinetics may vary among neurons, depending on factors such as the distance of the recorded cell from the slice surface (where the agonist ejection occurs) or the route of aCSF flow which removes the agonist. However, this agonist application system elicits stable currents up to several minutes, being thus suitable for the pharmacological analysis (Cucchiaroni et al, 2010;Guatteo et al, 1999;Ledonne et al, 2015;Tozzi et al, 2001). Agonist-induced currents were recorded in control conditions or in the presence of MK-801 (30 mМ), CNQX (30 mМ) and CPCCOEt (100 mM), bath-applied for 9e12 min, or in DL-TBOA (100 mМ, bath-applied for 6 min).…”

Natural toxins implicated in the development of Parkinson’s disease

“…Interestingly, GABAergic SNpc cells respond to BMAA with an AMPA-mediated inward current that is not associated with an intracellular calcium increase [Cucchiaroni et al 2010]. BMAA has been previously reported to activate mGluRs in hippocampal, striatal, and cerebellar neurons [Lobner et al 2007].…”

Interleukin-6 prevents NMDA-induced neuronal Ca2+overload via suppression of IP3 receptors

“…NMDA-evoked intracellular Ca 2þ overload is a major factor leading to excitotoxicity, by which neuronal apoptosis and necrosis occur in acute and chronic brain injuries and diseases, such as ischemia, trauma, epilepsy, amyotrophic lateral sclerosis, Alzheimer's disease and Parkinson's disease [19][20][21]. IL-6 attenuates glutamate-or NMDA-induced intracellular Ca 2þ overload and subsequently suppresses neuronal apoptosis and necrosis [14,18,22].…”