Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. We examined in vivo alterations in hippocampal neurotransmission in both young and aged PDAPP transgenic mice and nontransgenic littermates. We now report that in vivo abnormal neurotransmission in hippocampal circuits of PDAPP mice precedes beta deposition and neurodegeneration. These in vivo data provide the first evidence that dysfunction in hippocampal neuronal circuits may not be correlated with age-related extracellular beta plaque deposition.