層粘連蛋白A調控果蠅動作神經元突觸之可塑性生長

Abstract

神經細胞具有可塑性，可以藉由刺激經驗來調整其突觸功能及結構，這個特性通常被認為是動物學習與記憶行為上的細胞基礎。然而刺激經驗是經由那些下游途徑去達成突觸功能及結構上的改變，還尚未完全明瞭。LanA為果蠅連黏層蛋白中的α長鏈，已被證實會影響果蠅幼蟲動作神經元突觸在肌肉神經接合上的發育。果蠅幼蟲的動作神經元突觸表現高度的結構可塑性，當給予超過一定閾值的神經活化後，會刺激動作神經元在肌肉上長出更多的新生突觸結構造。我們在這發現，LanA會負向地調控引發新生突觸結形成所需的神經活化閾值。除此之外，高度的神經活化能在短時間內降低LanA在果蠅幼蟲神經元突觸上的表現量。Matrix metalloproteases (MMPs)的抑制劑能防止LanA受到神經活化的調控，且在實驗中添加MMP抑制劑也足以阻止神經活化所引發的新生突觸結。因此我們認為高度地神經活化，可能會刺激MMP，藉由其蛋白酶活性來分解及清除位於神經突觸附近的LanA分子，使得該處的神經可塑性不再被LanA所抑制，導致新生突觸結的產生。

Neurons have the ability to change their synaptic functions and structures in response to the experiences of hyperactivation or hypoactivation. This ability has been suggested as the cellular basis for learning and memory. Despite of its importance, the downstream mechanisms for synaptic activity to mediate the change remain elusive. LanA, an alpha subunit of laminins, has been shown to regulate the synaptic growth of Drosophila laral neuromuscular junctions (NMJs). Drosophila larval NMJs exhibit high degree of structural plasticity, forming new boutons in response to acute synaptic activation. I was able to assay the effect of LanA on the induction of new bouton by synaptic activation, and showed that LanA levels are negatively correlated with the activation threshold required for new bouton induction. Furthermore, synaptic activation acutely down-regulates the level of LanA at NMJs, and this down-regulation can be blocked by treatment of inhibitor of matrix metalloproteases (MMPs), which have also been shown to suppress the induction of new bouton during acute activation paradigm. Thus, I propose a model, in which activity-dependent MMP activation mediate the clearance of LanA at NMJs, thus releasing its inhibition on structural plasticity, promoting new boutons to form.