(−)Clausenamide facilitates synaptic transmission at hippocampal Schaffer collateral-CA1 synapses

Abstract

Clausenamide is a chiral compound isolated from leaves of the traditional Chinese herb Clausena lansium (lour) Skeels. It has been shown that (−)clausenamide, but not (+)clausenamide, improved learning and memory in amnesia animal models. However, the precise mechanism of clausenamide's actions remains unknown. Here we used an electrophysiological approach to observe the effect of (−)clausenamide on facilitating field excitatory postsynaptic potential (f-EPSP) in the CA1 area of hippocampal slices from rats. The results showed that (−)clausenamide enhanced synaptic transmission at doses 0.1, 1 and 10μM. The increase of f-EPSP induced by (−)clausenamide was completely inhibited by preincubation with nimodipine (L-voltage-dependent calcium channel blocker, 10μM), but there was no change when nimodipine was added after (−)clausenamide application. However, ryanodine (ryanodine receptors blocker, 100μM) attenuated the slope of f-EPSP before or after (−)clausenamide incubation. The data suggested that (−)clausenamide promoted calcium influx to trigger intracellular calcium release which was responsible for potentiating synaptic transmission. Intracellular calcium release induced by (−)clausenamide promoted the activation of CaMKIIα at concentrations of 0.1, 1 and 10μM, and pretreatment with KN93 (CaMKIIα inhibitor, 10μM) completely blocked the enhancement of synaptic transmission induced by (−)clausenamide. cAMP response element-binding protein (CREB) was activated by (−)clausenamide and inhibited by KN93 preincubation, but H89 (PKA inhibitor, 10μM) had no effect, indicating that (−)clausenamide facilitated synaptic transmission by a PKA-independent pathway. Collectively, (−)clausenamide facilitated synaptic transmission by promoting calcium influx to trigger intracellular calcium release, subsequently activating CaMKIIα-CREB signal pathway.