S. GELMAN1, J. PALMA1, A. GHAVAMI1
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.