突触的形成、成熟和功能依赖于神经元树突中的囊泡运输系统输送突触蛋白和膜组分。作为兴奋性突触的主要接收位点，树突棘结构和功能的可塑性是学习和记忆的分子细胞基础，而树突棘突触形成及神经活性依赖的突触可塑性中囊泡运输的作用及调控机制尚未阐明。我们的前期研究提示，动力蛋白dynein-dynactin的货物介导因子SNX6介导树突中囊泡运输。在中枢神经系统中SNX6基因敲除不仅使海马区CA1神经元顶端树突的树突棘密度降低，还导致了小鼠空间学习与记忆缺陷。由于在从胞内体到高尔基体的逆向囊泡运输中，细胞内膜系统中的磷脂分子PtdIns(4)P通过和SNX6相互作用精确调控动力蛋白对货物的卸载，我们计划运用细胞生物学和神经生物学手段，检测树突质膜及内膜系统中PtdIns(4)P对于SNX6介导的突触后蛋白如GluR1向突触位点靶向运输的调控作用，解析磷脂通过调节囊泡运输参与突触形成及可塑性的分子机制。

The formation, maturation and functioning of synapses rely upon targeted delivery of synaptic proteins and membrane components by the vesicular transport machinery in neuronal dendrites. As major synaptic sites for excitatory inputs, the structural and functional plasticity of dendritic spines is the cellular and molecular basis of learning and memory. However, roles of dendritic trafficking and underlying regulatory mechanisms during synapse formation and activity-dependent plasticity remains largely unknown. Our preliminary data suggest that SNX6, a cargo adaptor for the dynein-dynactin motor, mediates vesicular transport in dendritic shaft and spines. Ablation of SNX6 in mouse central nervous system causes not only a decrease in spine density in apical dendrites of hippocampal CA1 neurons, but also deficits in spatial learning and memory. Previously we have shown that in retrograde vesicular transport from endosomes to the trans-Golgi network, SNX6 mediates release of vesicular cargoes by dynein-dynactin at the target membrane via interaction with PtdIns(P), a Golgi-enriched phospholipid. In this study, In order to investigate role(s) of membrane lipids in dendritic trafficking during synapse formation and synaptic plasticity, we propose to employ cell biology and neurobiology approaches to determine regulatory function of PtdIns(4)P in dendritic plasma membrane and endomembranes in SNX6-mediated targeted delivery of postsynaptic proteins such as GluR1 to synaptic sites.