Astrocytes Mediate Hyperexcitability in Normal Neuronal Function During Tauopathy Disease Progression

During early stages of tauopathy disease progression, tau hyperphosphorylates and then mediates an increase in the release of the neurotransmitter glutamate. This increased glutamate release causes excessive neuronal activity called hyperexcitability. Hyperexcitability in turn induces the extracellular release of hyperphosphorylated tau causing it to spread to other neurons. Over time, the extracellular spread of hyperphosphorylated tau results in a buildup leading to neurodegeneration. However, neurons aren't the only cells in the brain that mediate the exctracellular spread of tau. Recently, neighboring cells, called astrocytes, have been shown to support extracellular tau spread by releasing the same tau to nearby neurons exacerbating disease progression. Understanding how astrocytes mediate extracellular tau spread is thus an important open question to address. We present our recent experimental results showing how astrocytes mediate extracellular spread of tau and supporting hyperexcitability in neuronal networks. We use normal hippocampal primary mouse neurons grown with primary astrocytes from a P301L mouse model. We show how P301L astrocytes mediate increased glutamate release in normal neurons equivalent to P301L neurons. This increase in glutamate release occurs across different P301L tau concentrations. Finally, we show how increased glutamate can be rescued by targeting presynaptic mechanisms of glutamate recycling.