P301L Tau Mediates Increased Glutamate Release in Hippocampal Neurons Via Increased VGLUT1 in Tauopathy Mouse Model

The molecular pathways that contribute to the onset of symptoms in tauopathy models, including Alzheimer’s Disease (AD), are difficult to distinguish because multiple changes can happen simultaneously at different stages of disease progression. Understanding the mechanistic pathways of early synaptic alterations is essential in order to understand how different processes can have confounding affects and still lead to neurodegeneration in AD and other neurodegeneratic diseases. Here we focus on an early onset rTg(Tau_P301L)4510 tauopathy mouse model that exhibits hyperexcitability in hippocampal neurons of adult mice that is correlated with presynaptic changes and increased extracellular glutamate levels. However, it is not clear if increased extracellular glutamate is caused by presynaptic changes alone, or if presynaptic changes are a contributing factor among other factors. We show that tau_P301L positive neurons exhibit a 40% increase in VGLUT1 per vesicle compared to tau_P301L negative littermates. Further, we use the extracellular glutamate reporter iGluSnFR to show that increased VGLUT1 per vesicle directly translates into a 40% increase in extracellular glutamate. Together, these results show that increased extracellular glutamate levels observed in tau_P301L mice are not caused by increased vesicle exocytosis probability but rather are directly related to increased VGLUT1 transporters per synaptic vesicle.