Summary of studies analyzing the effect of tau reduction on network excitability in Aβ mice and in WT mice
| Author(s) and publication year | Mouse model/ transgene(s) | Age/stage of pathology | Baseline neuronal network excitability status | Experimental paradigm and tau reduction strategy/effect of tau reduction on neuronal network excitability |
|---|---|---|---|---|
| Roberson et al. (2007) | hAPPJ20/tau+/+, hAPPJ20/tau+/−, hAPPJ20/tau−/−, tau+/+, tau+/−, tau−/−.hAPP(J20): hAPPSwe, hAPPInd, PDFG promoter | hAPP/tau+/+: 4–7 months, Aβ plaques, neurodegeneration | Increased in hAPP/tau+/+ | Experimental paradigm: in vivo PTZ-induced and kainate-induced seizure susceptibility evaluation. tau reduction achieved through crossing hAPPJ20 line with tau knock-out (tau−/−). Findings: tau reduction increased resistance to both PTZ-and kainate-induced seizures. Seizures were less severe in hAPP/tau+/– and hAPP/tau–/– mice than in hAPP/tau+/+ mice. Seizures were also less severe in tau–/– mice than in tau+/+ mice. The onset of seizure was also delayed by tau reduction. tau reduction also ameliorated learning and memory deficits in hAPPJ20 mice. |
| Roberson et al. (2011) | hAPPJ20/tau+/+, hAPPJ20/tau+/−, hAPPJ20/tau−/−, hAPPJ9/tau+/+, hAPPJ9/tau−/− tau+/+, tau−/−. | 7–14 months for in vivo EEG detection of frequency of epileptiform spikes: Aβ plaques, neurodegeneration. 5–8 months for in vivo PTZ-induced seizure susceptibility evaluation: Aβ plaques, neurodegeneration | Increased in hAPPJ20/tau+/+ and hAPPJ9/tau+/+ mice | Experimental paradigm: in vivo PTZ-induced seizure susceptibility evaluation. In vivo EEG detection of frequency of epileptiform spikes in freely moving mice. In vitro epileptiform discharges in area CA1 of the hippocampus after bicuculline administration in acute slices. tau reduction achieved via crossing hAPPJ20 or hAPPJ9 line with tau knock-out (tau−/−) mice. Findings: tau reduction decreased PTZ-induced seizure severity and frequency of generalized epileptiform spikes in hAPPJ20 mice. tau reduction also prevented bicuculline-induced epileptiform bursting in acute hippocampal slices from WT (tau−/−) and hAPPJ20 mice. |
| DeVos et al. (2013) | WT (C57BL/6J), tau−/− | 3–5 months, no pathology | Normal | Experimental paradigm: in vivo EEG recordings, baseline and after picrotoxin administered via reverse microdialysis. In vivo PTZ-induced seizure susceptibility evaluation. tau reduction was achieved via ASOs. Findings: reduction in normalized spike frequency after picrotoxin administration in ASO-treated WT mice and tau−/− as compared with controls. Total tau protein levels in the hippocampus of mice highly correlated with normalized spike frequency. PTZ-induced seizure severity was significantly reduced in ASO-treated WT mice. Seizure severity and tau protein levels correlated well in all tested mice. |
| Li et al. (2014) | tau+/+, tau+/−, tau−/−. (all on C57Bl/6J background) | 24 months, no pathology, age-appropriate cognitive function | Normal | Experimental paradigm: in vivo PTZ-induced seizure susceptibility evaluation. tau reduction achieved via genetic homozygous or heterozygous knock-out. Findings: PTZ-induced seizure severity was significantly reduced in tau knock-out aged mice. Also, aged tau+/− and tau−/− mice had longer seizure latencies than tau+/+ mice. |
| Ittner et al. (2010) | APP23 (APPSwe, Thy1 promoter), Δtau74 (amino acids 256–441 removed from the longest human tau isoform, htau40), tau−/−, Δtau74.tau−/−, APP23. Δtau74, APP23. tau−/−, APP23. Δtau74.tau−/− | APP23: 2–3 months, no plaques. Δtau74: 2–3 months, tau missorting, normal endogenous tau but negligible phospho-tau | Increased in APP23 mice | Experimental paradigm: in vivo PTZ-induced seizure susceptibility evaluation. tau reduction achieved via crossing APP23 line with Δtau74 or tau−/− mice. Findings: seizure severity was significantly reduced in Δtau74, tau−/−, and Δtau74. tau−/− compared with the WT, while the latency to develop severe convulsion was increased. APP23 mice presented with a reduced convulsion latency and showed the most severe seizure response. However, when APP expression was combined with Δtau expression or tau deficiency, this significantly decreased seizure severity, reduced fatality, and increased convulsion latency. The double mutant Δtau74.tau−/− prevented severe seizures better than Δtau74 or tau−/−alone, on both WT and APP23 backgrounds. |
Aβ, amyloid β; ASOs, antisense oligonucleotides; EEG, electroencephalogram; hAPP, human amyloid β precursor protein; PDGF, platelet-derived growth factor; PTZ, phenylenetetrazole; WT, wild type.