Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit

- Mutated hAPP in entorhinal cortex (EC) increased neuronal excitability in the EC.
- EC co-expression of hTau with hAPP significantly decreased such excitability.
- hAPP expression in EC produced synaptic downscaling of subicular neurons.
- Modeling shows that EC and SUB findings can be recreated by EC interneuron pruning.
- The effect of hTau expression in the EC produced decreased neuronal excitability.

The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP.