Executive dysfunction is associated with altered hippocampal-prefrontal functional connectivity in 3xTg Alzheimer's...

Executive dysfunction encompasses altered decision-making, attentional deficits, excessive risk-taking behaviours, and inefficient planning. Alongside memory loss, these cognitive deficits are amongst the most frequently reported symptoms of Alzheimer's disease (AD). Normal executive function depends on connectivity between the ventral hippocampus and medial prefrontal cortex (mPFC), yet abnormalities in this circuit and how such changes lead to cognitive dysfunction in AD have yet to be fully elucidated. Here, we show that 6-month-old male 3xTg AD mice display maladaptive decision-making in the rodent 4-Choice Gambling Task measure of executive function. Extracellular field recordings in the infralimbic cortex of age-matched 3xTg mice show layer-specific reductions in response amplitude and paired-pulse ratio compared to controls following activation of hippocampal input fibres, indicating changes to short-term hippocampal-prefrontal synaptic plasticity. These results therefore reveal a pre-clinical deficit in executive function that correlates with mPFC synaptic plasticity deficits in a mouse model for AD.