Entorhinal cortex (EC) is the initial brain region that suffers abnormal tau in Alzheimer's disease (AD). Whether overexpression of human tau (htau40) in EC disrupts cognitive function and synaptic plasticity in AD has not been fully elucidated. To investigate the effects of htau40 on the pathology and associated mechanisms of early stage of AD in mice, an adeno-associated virus-based htau40 transduced in medial EC (mEC) mouse model was established. The results showed that htau40 restrictedly expressed in mEC after transduction. The memory function and long-term potentiation (LTP) of dentate gyrus (DG) were significantly impaired by overexpression of htau40 in mEC after transduction at 3 and 6 months. However, the abnormities of neurons and neurotransmitters in mEC started at just 1 month after transduction. The resting membrane potential was increased and paired pulse facilitates was depressed, but the action potential amplitude, threshold, and half width did not alter after htau40 transduction at 1 month. The levels of inhibitory neurotransmitters were up regulated whereas level of lactate was decreased. Our study demonstrated that htau40 in mEC impaired cognition and synaptic plasticity of perforant path (PP)-DG, which simulated early stage of AD and elucidated the mechanism of that htau40 overexpression in mEC may be associated with the development of AD. (C) 2017 Published by Elsevier Inc.