Syringaresinol suppresses excitatory synaptic transmission and picrotoxin-induced epileptic activity in the hippocampus through presynaptic mechanisms

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.