Author ORCID Identifier
Date Available
7-8-2021
Year of Publication
2021
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Physiology
Advisor
Dr. Bret N. Smith
Co-Director of Graduate Studies
Dr. Steven Estus
Abstract
Tauopathies, including Alzheimer’s disease (AD), are devastating diseases with an immense burden on society which is predicted to increase in coming decades. In addition to progressive loss of memory and cognitive function, patients with tauopathies have a 6-10 fold increase in lifetime risk for seizures, and many are diagnosed with epilepsy. The presence of epileptiform activity on electroencephalogram (EEG) recordings from patients with AD predicts faster cognitive decline compared to patients without abnormal EEG readings. Electrophysiological measurements in murine models of AD have identified neuronal hyperexcitability. Furthermore, reducing tau phosphorylation or expression confers seizure resistance in animal epilepsy models. Although evidence suggests the presence of common mechanisms contributing to both tauopathy and epilepsy, more work is needed to understand how this interaction works and whether tau can be effectively targeted to improve patients’ lives. This study investigated the relationship between tauopathy using transgenic mice that expressed no tau protein (tau-/-) or expressed non-mutant, human tau protein without expressing murine tau (htau). The htau mice develop progressive tauopathy with age. Non-transgenic C57BL/6J mice were used as controls. Whole-cell patch-clamp electrophysiology was used to define tau’s role in neuronal excitability in vivo in dentate gyrus granule cells. Both transgenic mouse strains exhibited a lower frequency of evoked action potentials and reduced likelihood of neurotransmitter release from perforant pathway inputs as measured by the paired pulse ratio compared to control at 1.5 months of age, but these differences were lost with age. The similarities between the tau-/- and htau mice suggest that hyperexcitability is related to the amount of normally functioning tau rather than the presence of pathological tau, and that the presence of normal murine tau may influence the results of other studies involving models of tauopathy. Furthermore, tau’s role in epileptogenesis was studied using intrahippocampal injection of kainate (i.ie., IHK) to induce status epilepticus, a model that induces temporal lobe epileptogenesis, in tau-/-, htau, and C57BL/6J mice. The process of epileptogenesis appeared to be modified compared to control in both transgenic strains, but did not appear to be prevented. Compared to either tau-/- or C57BL/6J mice, htau mice experienced significantly greater mortality after IHK. Modifications in tau expression, wither deletion or humanization, partially abrogated synaptic excitability that developed following IHK.
In conclusion, this study showed that neuronal excitability is affected similarly by either deletion or humanization of tau, with the notable exception of survival after IHK. This study provides clearer understanding of tau’s role in acquired epilepsy and suggests novel therapeutics targeting tau may be effective for the treatment of epilepsy.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2021.271
Funding Information
This work was funded by National Institutes of Health [NINDS 1R01NS092552 (2017-2021), NINDS 5R01NS091329 (2017), NCATS TL1TR001997 (2018-2020), and NIGMS 1T32GM118292 (2017-2018)] and the Department of Defense [W81XWH-15-1-0551 (2017)].
Recommended Citation
Cloyd, Ryan A., "THE ROLE OF MICROTUBULE-ASSOCIATED PROTEIN TAU IN NEURONAL EXCITABILITY AND EPILEPTOGENESIS" (2021). Theses and Dissertations--Physiology. 51.
https://uknowledge.uky.edu/physiology_etds/51
