LAUSR

ABSTRACT Many neuromodulating drugs acting on the nervous system originate from botanical sources. These plant‐derived substances modulate the activity of receptors, ion channels, or transporters in neurons. Their properties make the substances useful for medicine and research. Here, we show that the plant lignan (+)‐syringaresinol (SYR) suppresses excitatory synaptic transmission via presynaptic modulation. Bath application of SYR rapidly reduced the slopes of the field excitatory postsynaptic potentials (fEPSPs) at the hippocampal Schaffer collateral (SC)‐CA1 synapse in a dose‐dependent manner. SYR preferentially affected excitatory synapses, while inhibitory synaptic transmission remained unchanged. SYR had no effect on the conductance or the desensitization of AMPARs but increased the paired‐pulse ratios of synaptic responses at short (20–200 ms) inter‐stimulus intervals. These presynaptic changes were accompanied by a reduction of the readily releasable pool size. Pretreatment of hippocampal slices with the Gi/o protein inhibitor N‐ethylmaleimide (NEM) abolished the effect of SYR on excitatory synaptic transmission, while the application of SYR significantly decreased Ca2+ currents and hyperpolarized the resting membrane potentials of hippocampal neurons. In addition, SYR suppressed picrotoxin‐induced epileptiform activity in hippocampal slices. Overall, our study identifies SYR as a new neuromodulating agent and suggests that SYR suppresses excitatory synaptic transmission by modulating presynaptic transmitter release. Highlights(+)‐syringaresinol (SYR) suppresses excitatory synaptic transmission.SYR reduces the probability of release and the readily releasable pool size.SYR decreases Ca2+ currents and hyperpolarizes the resting membrane potential.SYR attenuates picrotoxin‐induced epileptiform activity in the hippocampal CA1.