Axonal conduction velocity in CA1 area of hippocampus is reduced in a mouse model of Alzheimer's disease, rTg4510.

1PsychoGenics, Inc., Paramus, NJ, USA


We previously reported that conduction velocity (VC) of Schaffer collaterals in CA1 area of hippocampus is reduced in an age-dependent manner in two amyloid precursor protein transgenic mouse models, line 41 (APP Swe/Lon) and APP/PS1 (cross between tg-2576 (APPSwe) and a mutant PS1 (m146L) mouse). Here we asked whether similar deficit in VC is also present in a mouse model of tauopathy, rTg4510, which over-expresses microtubuleassociated protein tau carrying a P301L mutation. Hyper-phosphorylated tau disrupts axonal cytoskeleton and transport, potentially resulting in abnormal levels of Na+ and/or K+ channels and Na+/K+ – ATPases, which may contribute to changes in VC.


We measured VC of Schaffer collaterals in CA1 area of hippocampus of rTg4510 mice at 3 and 6 month of age. We used a transverse hippocampal slice preparation with two extracellular recording electrodes to capture propagation of compound action potentials (CAPs) elicited by a stimulating electrode in the presence of synaptic transmission blockers. VC (in μm/ms) was calculated as d/t, where d is the linear distance between recording electrodes (100μm-600μm) and t is the time of CAP propagation. We also compared VC deficits in rTg4510 mice with those reported by us previously in line 41 (3 and 6 mo old) and APP/PS1 (24 mo old) mice.


At 3 mo of age average VC was not different between WT, tTA controls, and rTg4510 mice. In older rTg4510 mice (6 mo), average VC was significantly reduced compared to age-matched WT (ΔVC∼22.8 μm/ms) and tTA controls (ΔVC∼21.7 μm/ms). VC deficit was more pronounced in this tauopathy model then in line 41 (6 mo old), where we reported ΔVC∼10.4 μm/ms. APP/PS1 exhibited comparable deficit in VC (ΔVC∼20.1 μm/ms) at a much older age (24 mo).


These data suggest that over-expression of mutant human Tau or APP genes results in a reduced axonal VC, potentially disrupting the timing of synaptic inputs. Reduction in axonal VC in both tauopathy and amyloidosis mouse models of AD, albeit to a different degree, points to functional commonality between these models. This deficit may alter temporal organization of hippocampal networks leading to cognitive and memory dysfunction commonly observed in AD mouse models.


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