Kosala Dissanayake

Synaptic vulnerability to excitotoxicity may be a common pathway to neurodegeneration in many neurodegenerative diseases, including motor neuron diseases such as Amyotrophic Lateral Sclerosis (MND/ALS), Alzheimer’s disease, Parkinson’s disease and Huntington disease. Therefore, understanding how excitotoxicity contributes to synaptic vulnerability and preventing it may help to prevent or retard the progression of these devastating diseases in the long run. Ca2+ dependent excitotoxicity leading to neuronal cell death is one of the common pathways hypothesised at both glutamatergic and cholinergic synapses. Therefore we are investigating how normal handling of intracellular Ca2+ is altered by excitotoxic triggers and, specifically, test the hypothesis that excitotoxicity at NMJs depends on either cytoplasmic increases in Ca2+ ions due to their release from the sarcoplasmic reticulum (Ca-induced Ca-release via ryanodine receptors) or failure to initiate relaxation (Ca2+ removal from cytoplasm via SERCA). I will use pharmacological interventions to separate out the fast and slow Ca2+ transients, in order to identify whether post-tetanic Ca2+ surges depend on either CaV 1.1 or dihydropyridine receptors (DHPRs) and ryanodine receptors, or DHPR and inositol trisphosphate receptors (IP3Rs). Alternatively, promoting initiation of relaxation via SERCA or other mechanisms (uptake via sarcolemmal Ca2+ transport proteins and mitochondrial uniporter) would results in reduction of Ca2+ surges. I will explore the possible pathways of Mg2+ mitigation of Ca2+. Finally, we are also investigating evidence for Ca2+ dependent excitotoxicity and degeneration by looking at human post-mortem in samples pesticide toxicity cases.