Axonal conduction velocity in CA1 area of hippocampus is reduced in mouse models of Alzheimer's disease

1PsychoGenics Inc., Montvale, NJ, USA


The timing of action potentials arrival at synaptic terminals partially determines the integration window of synaptic inputs and is important for information processing in the CNS. Therefore, axonal conduction velocity (Vc) is a salient parameter, influencing the timing of synaptic inputs. Even small changes in Vc may disrupt information coding in networks where accurate timing is crucial, adversely affecting such brain functions as cognition and memory. We asked whether changes in Vc might be present in genetic models of Alzheimer’s disease (AD), where cognitive function is disrupted.


We measured Vc in axons of Schaffer collaterals in CA1 area of hippocampus in two transgenic mouse models of AD that over-express β-amyloid, line 41 (6mo) and APP/PS1 (24mo). 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 (CNQX, APV, and picrotoxin). Vc (in μm/ms) was calculated as d/t, where d is the linear distance between recording electrodes (200μm-600μm) and t is the time of CAP propagation. Time interval (i.e. width) between positive and negative peaks of CAP (TCAP) was used to assess Vc heterogeneity among single axons. A ratio (TCAP2/TCAP1) of CAPs recorded at two positions was used as a measure of de-synchronization due to Vc variability.


Average Vc in line 41 was significantly reduced compared to WT (ΔVc∼10.4). Frequency distribution of Vc was significantly left-shifted (range=87.8-225.5 vs WT 123.4-218.6). The TCAP2/TCAP1 was increased compared to WT (1.9±0.2 (sem) vs WT 1.5±0.1), which is consistent with lower Vc of single units comprising CAPs. In a model with accelerated amyloidosis, APP/PS1, the slowing of Vc was more pronounced (ΔVc∼20.1). We observed a larger left-shift in distribution of Vc (range=85.7-216.1 vs WT 155.3-265.9) as well as a larger TCAP2/TCAP1 (2.2±0.3 vs WT 1.6±0.1), implying greater asynchrony among CA3 axons.


These data suggest that APP/PS1 mutations result in a reduced axonal Vc, potentially disrupting the timing of synaptic inputs. Temporal disorganization of hippocampal networks may lead to cognitive and memory dysfunction commonly observed in AD mouse models.


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