P301L tau Mediated Changes in Presynaptic Vesicle Recycling During Hyper-excitable states
Tau is a protein essential for neuronal function, but altered forms of tau lead to neurodegeneration and dementias called tauopathy. One form of altered tau called the P301L mutation is linked with human frontal temporal dementia (FTD). This tau is known to get into the presynapse during the later stages of the disease progression and slow release of the neurotransmitter glutamate that is essential for cognition and memory.
However, early stages of the same P301L tauopathy exhibit increased glutamate release resulting in hyper-excitable states (i.e. more communication). This leads to an unexpected contradiction where early disease stages exhibit increased synapse communication, whereas late stages exhibit reduced synapse communication.
Our lab explores the mechanics of vesicle recycling during these hyper-excitable states in order to find novel drug targets for treatment early during disease progression.
We recently showed that previously observed increase in the protein VGlut1 is the main causative pathway for increased glutamate release. We observed an increase in VGlut1 in neurons grown on coverslips (shown with fluorescence imaging above). Undergraduate students working in my lab then showed that the VGlut1 increases at the single vesicle level prior to any observed changes in presynaptic function (shown below).
We image the release of the neurotransmitter glutamate from hippocampal synapses to understand how tau-induced changes affect synaptic communication.
Lab Techniques and Approaches
Our lab utilizes a combination of Electron Microscopy, Fluorescence Microscopy, and Computational analysis to study molecular level changes in tauopathy mouse model of P301L as a function of age. This innovative combination of techniques and analysis provides a holistic understanding of mechanistic changes that occur during disease progression.
We focus on changes in presynaptic function of the hippocampus. The hippocampus is where memory and spatial maps are stored in the brain. Loss of hippocampal neuronal function results in loss of memory and cognition. Understanding changes in neurons of this region are thus paramount to understanding the progression of AD.
Chemical presynapses in the hippocampus rely on efficient recycling and use of neurotransmitter carrying vesicles. This recycling process requires a tremendous amount of energy that is supplied by mitochondria.
Presynaptic Vesicle Recycling changes in P301L:
We utilize high-resolution electron microscopy to obtain ultra-structural information about presynapses. By obtaining 3Dimensional structural information we can distinguish changes that occur in presynaptic vesicle distribution and use in P301L mice. By tracking this information as a function of age, we can then distinguish changes that occur during disease progression.
Mitochondrial changes in P301L
Electron Microscopy imaging of mitochondria in P301L expressing mouse hippocampal cells.
Mitochondria are known to change their function during disease progression in AD. We study these changes and correlate them with observed changes in presynaptic vesicle recycling. We can also correlate ultrastructural changes with observed mechanistic changes using fluorescence microscopy.
