Metformin enhances hippocampal excitatory synaptic transmission and preserves synaptic plasticity under amyloid-β oligomer-induced dysfunction.

Early stages of Alzheimer's disease (AD) are characterized by synaptic dysfunction and alterations in synaptic plasticity that precede neuronal loss. Soluble amyloid-β oligomers (AβOs) are important contributors to these early synaptic alterations by disrupting excitatory neurotransmission and impairing hippocampal function. Metformin (Met), a widely used antidiabetic drug, has recently gained attention for its potential neuroprotective properties; however, its effects on hippocampal synaptic transmission and plasticity under amyloid-induced stress remain incompletely understood. In the present study, we investigated the effects of orally administered Met (200 mg/kg/day) on basal excitatory synaptic transmission, presynaptic release probability, and long-term synaptic plasticity in hippocampal slices from rats subjected to stereotaxic injection of AβOs into the CA1 region. Using field electrophysiological recordings, we show that Met significantly enhances basal excitatory synaptic transmission, increases presynaptic release probability, potentiates long-term potentiation (LTP), and attenuates long-term depression (LTD). Notably, Met prevented the impairments in synaptic transmission and plasticity induced by AβOs, maintaining synaptic responses at levels comparable to those observed in control animals. Together, these findings indicate that Met modulates hippocampal synaptic function and preserves physiological forms of synaptic plasticity under amyloid-induced stress conditions. Our results identify synaptic transmission and plasticity as functionally relevant targets of Met action and support further investigation of Met as a potential strategy for preserving synaptic function during the early stages of AD.