Effects of the highly potent and specific NLRP3 inhibitor MCC950 on synaptic transmission and plasticity in the rat hippocampus (360G-Wellcome-207178_Z_17_Z)

Activation of the NLRP3 inflammasome results in the activation of caspase-1, which cleaves pro-IL-1beta into its active form, IL-beta. Excess IL-1beta has been shown to be involved in neurodegenerative diseases in the brain including Alzheimer’s and Parkinson’s disease. IL-1beta has also been shown to inhibit synaptic plasticity such as long-term potentiation (LTP) in the hippocampus. Recently a novel inhibitor of the NLRP3 inflammasome has been discovered namely, MCC950. To date little is know of its action in the central nervous system. We hypothesize that this novel inhibitor may be able to rescue the impairment of LTP caused by excess IL-1beta. Hippocampal slices will be perfused with LPS and hypoxia, activating the inflammasome and thus inhibiting LTP. Slices will be perfused with MCC950 to investigate if it can modulate this inhibitory effect of LPS and hypoxia on LTP. This study may show for the first time an important role for inflammasomes in synaptic plasticity. MCC950 could thus prove to be protective against cognitive decline in neurodegenerative diseases.