Week 8: Mechanisms Of Excitotoxicity

This week, I aim to provide a detailed explanation of the relationship between inhibiting potassium voltage-gated channels and the development of Parkinsonian symptoms/Parkinson’s Disease. 

To reinforce what has been previously discussed, the aim of recording the electrophysiological profile of a neuron that has been infused with an inhibitory drug, such as 4-Aminopyridine, is to examine the behavior of the membrane potentials. In last week’s post, I showed an image of a neuron that was infused with the drug and its corresponding behavior. The membrane potentials remained in a state of constant depolarization for a brief duration of time and began repolarizing as soon as the drug’s effect subsided. During that depolarization state, excitotoxicity would occur, which would ultimately lead to neuronal loss. 

Excitotoxicity is an occurrence that causes the death of dopaminergic neurons through the prolonged activation of glutamate receptors. Specifically, glutamate is utilized to activate ionotropic receptors such as N-methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and kainic acid (KA) receptors. NMDA receptors are highly permeable to calcium ions, so the continuous activation of these receptors could lead to apoptosis (cell death) and cellular toxicity. AMPA receptors are also highly permeable to calcium ions; however, the GluR2 subunit manages the selectivity of the number of ions flowing through the membrane. Lastly, the KA receptors also showcase the same permeability of calcium ions. What we can gather from this is that excessive depolarization can lead to neurodegeneration and the formation of neurodegenerative disorders. 

Given that drugs such as 4-Aminopyridine and environmental factors such as insecticides have been found to induce this phenomenon, my research endeavors to highlight the need for researchers to explore and develop alternatives and pharmacotherapies to tackle the diverse array of scenarios that can give rise to Parkinson’s Disease. 

1. https://onlinelibrary.wiley.com/doi/full/10.1002/ps.5516
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002277/ 

Next Week, I plan to give an update on my research paper. See you!