TRPM2 in the Central Nervous System: Physiological Role and Critical Regulatory Pathways

TRPM2 is a non-selective cation channel which is permeable to calcium. Although expression is highest in the brain, the physiological role for TRPM2 in neurons was unknown. Furthermore, our understanding of the pathways regulating TRPM2 channel function required further investigation. In this thesis, we identified that TRPM2 is required for NMDAR-dependent long-term depression (LTD). No change in NMDAR expression or function was observed following genetic deletion of TRPM2. Instead, the loss of NMDAR-LTD in TRPM2 knockout mice results from diminished GSK-3β activation. We next examined whether age in vitro could facilitate TRPM2 currents. We demonstrate that diminished glutathione with age results in the loss of basal TRPM2 channel inhibition. We subsequently demonstrate that TRPM2 currents are enhanced by oligomeric Aβ, a peptide proposed to initiate the majority of toxic effects observed in Alzheimer’s disease. Potentiation of TRPM2 may involve Fyn, a tyrosine kinase implicated in oxidative stress and neurotoxicity. We demonstrate that Fyn is capable of interacting with and phosphorylating TRPM2. Acute application of Fyn through the patch pipette potentiates TRPM2 currents, and a Fyn(39-57) mimetic peptide significantly attenuates currents in cultured hippocampal neurons. These results are the first to establish a role for TRPM2 in neurons, and also implicate TRPM2 in neurodegenerative disorders such as Alzheimer’s disease