Tau deletion results in sex-dependent modulation of synaptic weakening in rat hippocampus

Ralph, L. T.; Tidball, P.; Salter, E. W.; Park, B.; Zhang, L.; Wang, M.; Joe, L. A.; Thacker, J. S.; Choi, S.-L.; Kadia, A.; Jin, F.; Tian, M.; Bradley, C. A.; Fraser, P. E.; Jia, Z.; Schmitt-Ulms, G.; Gertsenstein, M.; Nutter, L. M. J.; Georgiou, J.; Collingridge, G. L.

doi:10.1101/2025.08.07.665155

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bioRxiv · 10.1101/2025.08.07.665155

Tau deletion results in sex-dependent modulation of synaptic weakening in rat hippocampus

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Abstract

Tangles, a defining characteristic of Alzheimers disease (AD), are composed principally of hyperphosphorylated and misfolded tau species. However, dysregulation of tau precedes tangle formation by many years and is associated with cognitive decline, the best functional correlate of which is synaptic weakening and eventual synaptic loss. Although tau is present at synapses, its normal synaptic function is poorly understood - information vital to the rational development of tau-modifying therapies. Since rats have a greater cognitive repertoire than mice and display more robust signs of tau pathology in AD models, we developed a tau knockout (Mapt-/-) rat to investigate the impact of tau elimination on synaptic function. We observed that long-term depression (LTD), a form of synaptic weakening, is enhanced in the hippocampus of male, but not female, rats. This enhanced LTD was dependent on the synaptic activation of group I metabotropic glutamate receptors and involved altered synaptic actin polymerization. These studies therefore provide mechanistic insights into how tau modulates synaptic function via regulation of the actin cytoskeleton. Our findings are relevant to the understanding of the physiological roles of synaptic tau, the functional consequences of tau-lowering therapies, and the influence of sex in AD susceptibility.

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Ralph, L. T., Tidball, P., Salter, E. W., Park, B., Zhang, L., Wang, M., Joe, L. A., Thacker, J. S., Choi, S.-L., Kadia, A., Jin, F., Tian, M., Bradley, C. A., Fraser, P. E., Jia, Z., Schmitt-Ulms, G., Gertsenstein, M., Nutter, L. M. J., Georgiou, J., Collingridge, G. L.. 2025-08-07. Tau deletion results in sex-dependent modulation of synaptic weakening in rat hippocampus. https://doi.org/10.1101/2025.08.07.665155

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